Caballero B. (ed.) Encyclopaedia of Food Science, Food Technology and Nutrition. Ten-Volume Set

Подождите немного. Документ загружается.

in the presence of bile enabling lactose to enter more

freely and be hydrolyzed. Thus, the mechanism

whereby cells of Lactobacillus acidophilus can allevi-

ate the problems of lactose maldigestion is similar to

that of yogurt. However, Lactobacillus acidophilus

has the added advantage that it can grow in the

presence of the bile, and so new cells can be produced

during its growth in the intestine, providing even

more of the enzyme necessary for hydrolyzing lactose.

When preparing a product to which cells Lactobacil-

lus acidophilus are added, it is important that the cells

have been grown in a medium containing lactose as a

sugar source to insure that cells contain adequate

levels of the enzyme b-galactosidase. If not, the

amount of enzyme probably will be too low to

produce the desired benefit with regard to lactose

maldigestion as rapidly as desired.

Hypocholesterolemic Actions

0013 The risk of coronary heart disease in hypercholes-

terolemic persons can be significantly reduced by

lowering serum cholesterol levels. Germ-free animals

on an elevated cholesterol diet accumulate approxi-

mately twice as much cholesterol in the blood as

conventional animals on a similar diet. This suggests

the possibility that microorganisms in the intestinal

tract can influence serum cholesterol levels. Con-

sumption of organisms such as Lactobacillus acid-

ophilus can aid in the control of serum cholesterol

levels in humans. Two studies published in the 1970s

showed this to occur. In one of the studies, infants fed

a formula supplemented with Lactobacillus acido-

philus exhibited reduced serum cholesterol levels as-

sociated with increased numbers of lactobacilli in the

feces, compared with infants receiving the control

formula. This suggests that the lactobacilli may be

associated with the reduction of serum cholesterol

levels. In another study, a group of men fed milk

fermented by the natural flora in raw milk exhibited

unexpected reduced serum cholesterol levels. The fer-

mentation apparently included what was described as

a culture of Lactobacillus, although the organism was

not identified.

0014 Because of these studies, considerable research has

focused on the potential for Lactobacillus acidophilus

or related bacteria to exert beneficial influences on

serum cholesterol levels. Lactobacillus acidophilus

growing in a laboratory medium supplemented with

cholesterol and bile salts under anaerobic conditions

will assimilate cholesterol. This ability to assimilate

cholesterol varies tremendously among strains of this

species of bacteria. Results from a feeding trial using

pigs on a high-cholesterol diet as an animal model

revealed that supplementation of the diet with a strain

of Lactobacillus acidophilus that assimilated choles-

terol during growth in a laboratory medium had a

significant beneficial effect on serum cholesterol,

whereas a strain that did not assimilate cholesterol

during growth in a laboratory medium did not. This

suggests the importance of screening cultures for use

as a probiotic to produce a beneficial effect on serum

cholesterol levels. In another feeding trial involving

pigs with diet-induced hypercholesterolemia, animals

receiving cells of Lactobacillus acidophilus exhibited

a significant positive correlation between the reduc-

tion of serum cholesterol levels and the concentration

of cholic acid in the serum. The decline in serum

cholesterol was initiated more rapidly and reached a

significantly lower level in the animals fed the

lactobacilli than in those not fed the lactobacilli.

Such data suggest the possibility that the lactobacilli

interfered with the enterohepatic circulation of bile

acids, which can be an important factor in reducing

serum cholesterol levels. This also suggests another

activity of the lactobacilli, which may be important in

controlling serum cholesterol levels. Lactobacillus

acidophilus has the ability to deconjugate bile acids

through the action of bile salt hydrolase. Free bile

acids being less well absorbed from the small intestine

than conjugated acids are more likely to be excreted

from the body. Replacement of these excreted bile

acids involves the synthesis of new bile acids from

cholesterol in the body. This has a tendency to lower

the cholesterol pool in the body. This represents the

major pathway for removing cholesterol from the

human body. An additional advantage for the decon-

jugation is that free bile acids do not support the

absorption of cholesterol for the intestinal tract as

well as conjugated acids.

0015The mechanism whereby consumption of fer-

mented milk products containing cells of Lactobacil-

lus acidophilus or other probiotics may reduce levels

of serum cholesterol appears to include their ability

to assimilate cholesterol and/or deconjugate bile

acids (Table 4). Some of the cholesterol assimilated

by Lactobacillus acidophilus is incorporated in the

cellular membranes of the organisms. Bifidobacter-

ium longum also can incorporate some cholesterol

into its membrane, but Lactobacillus casei does not.

All three species have the ability to deconjugate bile

salts.

tbl0004Table 4 Activities of probiotic cultures important for imparting

a hypocholesterolemic effect

. Assimilation of cholesterol

. Deconjugation of bile salts

PROBIOTICS 4795

Control of Colon Cancer

0016 Some lactic acid bacteria can produce anticarcino-

genic or antimutagenic compounds, which can result

in the inhibition of some types of tumor cells in

animals. For example, rats that had been implanted

with ascites tumor cells and fed milk fermented with

Lactobacillus acidophilus exhibited a lower prolifer-

ation of tumor cells than those in the control group.

The conclusion was that the Lactobacillus species

produced substances during growth in the intestine

that was antagonistic toward the proliferation of these

tumor cells.

0017 Other studies have shown that certain fermented

milks have a beneficial influence on the proliferation

of colon tumor cells in rats. Feeding rats cells of

Lactobacillus reduced the activity of three enzymes

capable of converting procarcinogens into carcino-

gens in the intestinal tract. Similar results have been

shown in human studies. These enzymes were b-

glucuronidase, azoreductase, and nitroreductase. Re-

duction of the level of activity of these enzymes in the

intestinal tract can reduce the chances of carcinogens

being formed. The enzymes apparently are of micro-

bial origin. Thus, the potential anticarcinogenic ac-

tivity of feeding Lactobacillus acidophilus may, in

this case, be related to the control of undesirable

microorganisms in the intestinal tract. In other stud-

ies, the consumption of milk containing cells of

Lactobacillus casei activated macrophages in mice.

This observation was based on increases in enzyme

activity associated with macrophages. This suggests

another potential means, whereby the consumption

of a selected probiotic culture may influence prolifer-

ation of tumor cells in the body.

Other Benefits

0018 One of the main interests in the livestock industry in

using probiotic bacteria as feed supplements is to

improve nutrient utilization resulting in improved

growth and/or feed efficiency of the livestock. While

there is great interest in this area, there is very little

evidence reported in the scientific literature to indi-

cate how such benefits might occur. It is possible that

such benefits can result from the action of certain

enzymes associated with the probiotic bacteria. This

could be similar, for instance, to the beneficial effect

of yogurt bacteria and Lactobacillus acidophilus on

lactose maldigestion in humans that results from

b-galactosidase associated with the bacterial cells.

Selection of a culture of Lactobacillus acidophilus

with a high level of amylase activity for inclusion as

a probiotic in the diet of young pigs can improve

starch utilization in the young animal. In a feeding

trial involving the use of such a culture, improved

growth and feed efficiency of weaning aged pigs

were observed as a result of including the selected

culture in the diet. The benefit was attributed to the

amylase activity of the culture. It is possible that other

enzymes that could improve the digestion of other

nutrients may be present in some bacteria used as

probiotics that could result in improved growth and

feed efficiency of the livestock. Of course, the im-

proved growth may relate to the control of undesir-

able microorganisms in the animal’s intestinal tract.

There is also interest in the livestock and pet-food

industries in using probiotics to help control intestinal

infections in animals.

Selection of Probiotic Culture

0019While there are a number of potential benefits from

the inclusion of a probiotic culture in the diet, it is

essential that a culture be properly selected for such

use. One culture, that is one strain of one species,

should not be expected to provide all of the potential

benefits that might be derived from probiotics. To

help insure that the culture is successful and has a

positive effect, certain requirements are to be met

(Table 5). Since, in most cases, the sight of action of

the probiotic organisms is the intestinal tract, it is

generally accepted that the organism should be a

normal inhabitant of the intestinal tract. There is

strong evidence in the literature indicating that

many of these probiotic bacteria exhibit host specifi-

city; for example, a strain of Lactobacillus acido-

philus originating in the intestinal tract of a calf

should not be expected to function equally well in

the intestinal tract of a pig or of a human. Thus, it is

desirable to use a selected strain of bacteria that ori-

ginated in the host species for which the product is to

be used. If it is to be used as a probiotic for humans,

it is highly desirable that the probiotic organism ori-

ginated in the human intestines. In order to avoid

problems with regulatory agencies, it is desirable

that the organism of choice has a history of having

been used for producing fermented food products.

tbl0005Table 5 Important factors to consider in selection of a probiotic

culture

. Normal inhabitant of intestine

. Host specificity

. Acid tolerance

. Bile tolerance

. Stability during production and delivery

. Production of desired health/nutritional benefit

. One strain would be unlikely to provide all possible benefits

4796 PROBIOTICS

The organism should be resistant to gastric acidity to

survive passage through the stomach. The main or-

ganisms considered for use as probiotics (i.e., lacto-

bacilli) are acid-tolerant. However, resistance to

acidity varies among strains and species, so it must

be considered. If the organism is expected to grow

and function in the intestinal tract, it must have a

certain degree of bile tolerance. The bile resistance

based on the ability of the organism to grow in the

presence of bile acids varies tremendously among

strains of each species of probiotic bacteria. The min-

imum level of bile tolerance required is not known,

but it is suggested that the most bile-resistant strain

that will provide the desired benefit be selected. The

probiotic culture must be stable during production

and storage of the food or feed containing it. This is

often the most challenging factor in providing a pro-

biotic organism that has adequate levels of viability at

the time of consumption. The most important char-

acteristic of course is that the probiotic culture pro-

duce the desired effect. Therefore, it is desirable that

some sort of laboratory screening test for the desired

effect be implemented. This is not always easy. How-

ever, if the organism for instance is to be used for

improving lactose utilization, it would be desirable

to select one having a high level of b-galactosidase

activity. If it is to be used for controlling serum chol-

esterol levels, it is desirable that the organism not only

assimilate cholesterol but also have a high degree of

ability to deconjugate bile acids. In order to develop

useful screening tests, it is of course essential that we

understand how the probiotic organism functions to

provide the desirable benefit. In many cases, we

simply do not know the answer to this mechanism

at this point.

0020 A major factor in selection of a specific organism

for use as a probiotic is to remember that one strain

should not be expected to provide all potential bene-

fits. Far more is required in the selection process than

to select a culture just because it is Lactobacillus

acidophilus, for example. There is a great variation

among strains of this bacterial species. Such variation

also occurs among strains of other species of probio-

tic bacteria.

Dietary Delivery of the Probiotic

0021 If the probiotic organism is expected to provide its

benefit during growth and action in the intestinal

tract, it is reasonable to assume that the organism

must be viable at the time of consumption. It is also

desirable and recommended that the probiotic be

consumed on a continuing basis. The numbers of

viable probiotic bacteria required in a food or feed

product to provide the benefit are not known. The

actual numbers required probably will vary with the

organism and the expected function. Some have sug-

gested, particularly with regard to milk products,

that the probiotic should be present at a level of one

to two million per milliliter; however, these numbers

are not based on scientific data but are based more on

an economic situation reflecting the cost of the or-

ganism. Research is needed to answer the question

with regard to the optimum numbers required. It is

essential that the organism be stable and that the

desired characteristics be maintained during the pro-

duction of the probiotic culture, during its storage,

and delivery in the food or feed. This is often the

greatest challenge in the use of probiotic bacteria.

The stability of the organism during storage and

delivery can be greatly influenced by the conditions

under which the bacteria are grown. For instance, the

growth of Lactobacillus acidophilus at pH 5 has

resulted in cultures that are more stable during stor-

age when added to refrigerated milk than the same

cultures grown at a higher pH. The storage stability,

especially during frozen and refrigerated storage,

varies among strains of a given bacterial species

used as a probiotic. Thus, this becomes a factor

to consider in selecting the organism for use as a

probiotic.

0022The use of probiotic bacteria such as Lactobacillus

acidophilus in conjunction with yogurt can be accom-

plished by either including the probiotic as part of the

starter culture or adding cells of the probiotic bacteria

after the product has been manufactured. Of course,

it would be desirable to use the probiotic as part of

the inoculum (i.e., starter culture) used in the manu-

facture of yogurt in order to yield higher numbers of

the probiotic bacteria during the incubation period

for the fermentation. However, most of the probiotic

bacteria do not grow well under such conditions, and

very little increase in numbers is achieved during the

incubation process involved in the manufacture of

yogurt. Research is needed to provide means of in-

creasing the numbers of probiotic bacteria that grow

during the manufacture of a product such as yogurt

when the organism is used as a part of the inoculum

for manufacturing the fermented milk. In summary,

once a desired probiotic culture has been selected, it is

important to develop procedures for producing the

culture, storing the culture, and delivering the culture

in the food or feed without damaging the desired

characteristics.

See also: Bifidobacteria in Foods; Cholesterol:

Properties and Determination; Role of Cholesterol in

Heart Disease; Colon: Cancer of the Colon; Immunology

of Food; Lactic Acid Bacteria; Lactose; Salmonella:

Salmonellosis; Staphylococcus: Food Poisoning

PROBIOTICS 4797

Further Reading

Bezkorovainy A and Catchpole RM (1989) Biochemistry and

Physiology of Bifidobacteria. Boca Raton,FL: CRC Press.

Fuller R (ed.) (1992) Probiotics the Scientific Basis. New

York: Chapman & Hall.

Gilliland SE (1990) Health and nutritional benefits from

lactic acid bacteria. FEMS Microbiology Reviews 87:

175–188.

Klein G, Pack A, Bonaparte C and Renter G (1998) Tax-

onomy and physiology of probiotic lactic acid bacteria.

International Journalof FoodMicrobiology41:103–125.

Ouwehand AC, Kirjavainen PV, Shortt C and Salminen S

(1999) Probiotics: mechanisms and established effects.

International Dairy Journal 9: 43–52.

Robinson RK (ed.) (1991) Therapeutic Properties of Fer-

mented Milks. Barking, UK: Elsevier Science.

Sissons JW (1989) Potential of probiotic organisms to pre-

vent diarrhoea and promote digestion in farm animals –

a review. Journal of the Science of Food and Agriculture

49: 1–13.

Tamine AY and Robinson RK (1999) Yoghurt Science and

Technology,2

edn. Boca Raton, FL: CRC Press.

Process Control See Plant Design: Basic Principles; Designing for Hygienic Operation; Process Control

and Automation; Instrumentation and Process Control

Processed Cheese See Cheeses: Types of Cheese; Starter Cultures Employed in Cheese-making;

Chemistry and Microbiology of Maturation; Manufacture of Extra-hard Cheeses; Manufacture of Hard and Semi-

hard Varieties of Cheese; Cheeses with ‘Eyes‘; Soft and Special Varieties; White Brined Varieties; Quarg and

Fromage Frais; Processed Cheese; Dietary Importance; Mold-ripened Cheeses: Stilton and Related Varieties;

Surface Mold-ripened Cheese Varieties; Risk Assessment

PROSTAGLANDINS AND LEUKOTRIENES

S Katayama, Saitama Medical School, Iruma-gun,

Saitama, Japan

J B Lee, State University of New York, New York, USA

Background

0001 Prostaglandins (PGs) were discovered in the 1930s

and were first chemically isolated and identified in

sheep seminal vesicles and renal medulla in the 1960s.

Although together with thromboxanes (TXs) and

leukotrienes (LTs), the PGs possess the most potent

and most divergent biological activities of any natur-

ally occurring compounds, their true physiological

role in many instances remains unknown. From a

pathophysiological viewpont, an absolute or relative

deficiency of PGs relative to TXs has been implicated

in the etiology of hypertension, thrombosis, and

atherogenesis for many years. Since PGs and TXs

are derived from essential fatty acids, the role of

dietary intake of these fatty acids in PG and TX

production, particularly in relation to cardiovascular

system, will be examined. The possible role of dietary

essential fatty acids on LT and PG production in rela-

tion to inflammation, the immune system, and gastric

function will also be discussed.

Chemistry

0002In the 1930s, it was reported that fresh human semen

causes rhythmic contractions of human endomet-

rium. The active substance was called ‘prosta-

glandin.‘ In the 1960s, PG was determined to be a

mixture of biologically active compounds, which

were isolated from sheep seminal vesicles and identi-

fied as PGE

1–3

and PGF

1–2

. These compounds were

independently isolated from extracts of rabbit kidney

4798 PROSTAGLANDINS AND LEUKOTRIENES

medulla and identified as PGA

, PGE

, and PGF

Later, in 1975, the compound TXA

, which is a

potent vasoconstrictor and platelet aggregant, was

isolated, and in 1976, prostacyclin (PGI

) was dis-

covered. Prostacyclin is synthesized mainly by endo-

thelial cells, prevents platelet aggregation, and is

vasodilatory. Studies of the slow-reacting substance

of anaphylaxis (SRS-A) showed that it was composed

of certain LTs, which are products of leucocyte mem-

brane arachidonate.

0003 The PGs are composed of a basic 20-carbon fatty

acid chain containing a cyclopentane ring, the so-

called hypothetical prostanoic acid. The carbons are

numbered 1–20 from the carboxyl to the terminal

group. The designations of PGE

, PGE

, and PEG

refer only to the number of double bonds in the

aliphatic side-chains. The PG

s are the most abun-

dant naturally occurring class. For PG

s, the precur-

sor is 8,11,14-eicosatrienoic acid (dihomo-g-linolenic

acid), and for PG

s, the precursor is 5,8,11,14-

eicosatetraenoic acid (arachidonic acid). The PG

can be formed from 5,8,11,14,17-eicosapentaenoic

acid (EPA).

0004 The LTs were named because they were discovered

in leucocytes and because the common structural

feature is a conjugated triene. Various members of

the group have been designated alphabetically, and

the subscript denotes the number of double bonds.

Analysis of Prostaglandins and

Leukotrienes

0005 Prostaglandins and leukotrienes are present in many

different biological samples, including plasma. How-

ever, eicosanoid quantification in the peripheral

circulation does not accurately reflect in vitro biosyn-

thesis and disposition because of rapid turnover, low

concentration, metabolism by the lung and liver, and

sample processing problems. For example, plasma

concentrations of PGE

and TXB

determined by

gas chromatography have been reported to be 12

and several picograms per milliliter, respectively.

Urinary samples can be utilized to evaluate in vivo

PGs or LTs for the kidneys, whereas pleural fluids or

bronchial lavages can be used to evaluate pulmonary

production. The most accurate reflection of local

synthesis is obtained by incubations of slices or

homogenates of specific cells and/or tissues with

measurement of PG, TX, or LT production in vitro.

0006 The most precise method to determine PGs and LTs

is undoubtedly gas chromatography linked to mass

spectrometry. However, this type of analysis is not

widely available. Radioimmunoassay using a specific

antibody against various PGs or LTs and

H- or

125

I-

labeled tracer are available, highly specific, sensitive,

and relatively inexpensive, and have been widely

utilized for eicosanoid analysis.

0007Prior to radioimmunoassay, extraction of arachi-

donic acid metabolites from plasma, urine or tissue

homogenates may be required. The most common

method is to extract acidified aqueous solution with

an oraganic solvent such as diethylether or ethyl

acetate, followed by purification by column chroma-

tography with a octadecylsilyl (ODS) silica (SEP-PAK

C-18) cartridge, silicic acid or sometimes by high-

performance liquid chromatography.

Biosynthesis of Prostaglandins and

Leukotrienes

0008Arachidonic acid and its metabolite byproducuts (the

arachidonic acid cascade) are important mediators of

a number of physiological phenomena. As shown in

Figure 1, the rate-limiting step in the formation of the

metabolites of arachidonic acid seems to be the initial

step, i.e., the release of free arachidonic acid from the

cell membrane phospholipid pool mediated through

activation of phospholipase A

. Phospholipase C may

play another role in arachidonic acid release through

liberating a diglyceride, which is then hydrolyzed by

another lipase to yield arachidonic acid. Following

the release of arachidonic acid, enzymes are involved

in its subsequent metabolism. Prostaglandin synthase,

i.e., cyclooxygenase (COX), is a key enzyme in con-

trolling the extent of prostanoid biosynthessis. It pos-

sesses two enzymatic activities: COX activity, the

conversion of arachidonic acid (AA) to PGG

and

peroxidase activity, the conversion of PGG

PGH

catalyzing a two-electron reduction of PGG

to PGH

. PGH

is the common precursor for a

number of biologically important prostanoids, i.e.,

PGI

, TXA

, PGE

, PGD

, and PGF

, the formation

of which occurs through the action of the respective

synthetase called PGI synthase, TXA synthase, PGE

synthase, PGD synthase, and PGF synthase. COX is

distributed in most mammalian tissues. Two isoforms

of COX have been identified and cloned. COX-1,

originally cloned from ram seminal vesicles and sub-

sequently from mouse tissues and human endothelial

cells and platelets, is considered to be constitutive,

whereas COX-2, cloned from chicken embryonic

fibroblasts and mouse 3T3 fibroblasts, is highly

inducible. COX-1 activity is inactivated by aspirin

through acetylation of the serine residue and in-

hibited by other nonsteroidal antiinflammatory

drugs (NSAIDs), whereas COX-2 is inhibited by glu-

cocorticoids. Various biological activities are due to

binding of prostanoids to the receptors on the cell

surface. With the advent of the molecular biology

technique, eight prostanoid receptors have been

PROSTAGLANDINS AND LEUKOTRIENES 4799

cloned so far; TP, IP, FP, DP and four classes of EPs

(EP

,EP

,andEP

). Prostanoid receptors have

seven transmembrene domains and are members of

the superfamily of the rhodopsin receptor. These re-

ceptors are classified into three groups; IP, DP, EP

and EP

are the stimulatory receptors, which generate

cAMP, resulting in vasodilatoion; TP, FP, and EP

are

the G protein-linked receptors that increase intracel-

lular Ca

2þ

concentration, resulting in vasoconstric-

tion; and EP

is an inhibitory receptor, which inhibits

the elevation of cAMP, resulting in vasodilation.

0009 In the second pathway of arachidonic acid metab-

olism, 5-lipoxygenase forms a series of products

named LTs, as illustrated in Figure 1. 5-Hydroper-

oxyeicosatetraenoicacid (5-HPETE) may be enzyma-

tically dehydrated to LTA

(5(S)-trans-oxido-7,

9-trans-11, 14-cis-eicosa-tetraenoic acid). Subsequent

enzymatic hydrolysis of LTA

results in LTB

(5(S)-

12(R)-dihydroxy-6-cis-8, 10-trans-14-cis-eicosa-

tetraenoic acid). LTA

also reacts with sulfydryl com-

pounds by addition of gluthathione (Glu-Gys-Gly) by

glutathione-(S)-transferase, yielding LTC

(5(S)-glu-

tathionyl-7, 9-trans-11, 14-cis-eicosatetraenoic

acid). LTD

can be then produced from LTC

through

elimination of glutamyl residue by a g-glutamyl trans-

peptidase. The remaining peptide bond in LTD

hydrolyzed to give LTE

by a dipeptidase.

Physiological Action of PGs and LTs

0010The relative amounts of compound formed depend on

the tissue or cell being studied. When platelets are

activated by collagen or thrombin, unstable TXA

predominant, resulting in a rapid and irreversible

aggregation of platelets and contraction of vascular

smooth muscle cells. However, vascular endothelial

COOH

OOH

OCH

P O X

−

LTA

LTC

LTB

COOH

S Cys Gly

Glu

OOH

15-HPETE

5-HPETE

OH OH

12-HPETE

arachidonic acid

5, 15-diHPETE

HOO

Phospholipids

COOH

11-epi-PGF

2α

COOH

PGG

PGD

OOH

COOH

PGE

COOH

PCH

TXA

COOH

PGF

COOH

PGI

LTD

COOH

S Cys Gly

fig0001 Figure 1 Metabolic pathways of prostaglandin (PG) and leukotriene (LT) from arachidonic acid. The name of enzyme that catalyzes

each step is as follows: 1, phospholipase A

; 2, cyclooxygenase; 3, PGD synthase; 4, PGE synthase; 5, PGF synthase; 6, PGI synthase; 7,

TXA synthase; 8, 5-lipoxygenase; 8

, dehydrase; 9, hydolase; 10, glutathione-S-transferase; 11, 12-lipoxygenase; 12, 15-lipoxygenase.

4800 PROSTAGLANDINS AND LEUKOTRIENES

cells form unstable PGI

, which has a potent

vasodilating and antiaggregatory action similar to

stable PGE

, Neutrophils as well as monocytes or

macrophages produce PGE

, whereas PGD

formed in mast cells and basophils. In kidneys, renal

interstitial cells and collecting duct cells synthesize

PGE

, collecting dust cells synthesize PGE

, the

renovasculature endothelia synthesize PGI

, and

glomerular mesangial endothelia from PGF

.In

addition to PGE

, other PGs are also produced in

the gastrointestinal tract. PGE

, PGE

, and their

analogs, administered exogenously, suppress gastric

acid secretion and possess the property of protecting

the gastric mucosa against necrotizing agents such as

absolute ethanol or hydrochloric acid (cytoprotec-

tion). This is the reason why NSAIDs cause a variety

of problems in the gastrointestinal tract including

irritation and ulceration of the stomach. Since

COX-1 appears to play a major role, treatment with

COX-2 selective inhibitors appears to be associated

with less gastrointestinal damage than conventional

NSAIDs.

0011 Prostaglandins play many physiological roles in

human reproduction, e.g., menstrual regulation,

pregnancy, and induction of labor. PGE

, PGE

,or

their analogs are now widely used clinically for in-

duction of labor or abortion. PGE

and PGI

produce

or augment vasodilation and enhance bradykinin or

serotonin-induced pain, resulting in redness, heat,

swelling, and pain in the inflammatory processes.

PGs such as PGE

and PGI

have also been shown

to increase during pyrogen-induced fever. In fact,

PGE

administered into the hypothalamus increases

body temperature, whereas PGD

deceases body tem-

perature, indicating a possible role of PGs in human

thermoregulation. PGs, TXs, and some monohy-

droxy derivatives of arachidonic acid (hydroxyeico-

satetraenoic acids) also have chemotactic effects on

polymophonuclear leucocytes. LTB

is chemotactic

not only for neutrophils and eosinophils but also for

monocytic macrophages. These phenomena are con-

sidered to be the initial events of the inflammatory

response. Polymorphonuclear leucocytes only survive

for hours in the inflammatory area, whereas mono-

cytes may stay for weeks and finally may be trans-

formed to fibroblasts, initiating the repair process of

the wounds. Furthermore, monocytes can present

antigens to cells capable of producing antibodies

and can synthesize all the members of the arachidonic

acid cascade. Monocytes are also capable of forming

interleukin, interferon, complement, and protease, all

of which participate in tissue disruption. The lip-

oxygenase system is more important in subacute and

chronic inflammation, whereas the COX system

produces or modulates acute inflammation. The

antiinflammatory action of aspirin, indomethacin,

and other nonsteroidal antiinflammatory agents is

produced almost entirely by PG synthesis inhibition,

as shown by studies revealing inhibition of PG-

cyclooxygenase with aspirin.

0012LTC

,LTD

,LTE

, and their trans isomers do not

have any effects on chemotaxis, enzyme release, or

leucocyte aggregation. However, they possess potent

biological activities, which were formerly attributed

to SRS-A release from sensitized lungs treated with a

specific antigen. These compounds may be important

mediators in asthma and other acute hypersensitivity

reactions. Contraction of guinea-pig ileum and other

smooth muscle by LTs exhibits a slow onset and

relaxation, which is the basis of the original designa-

tion as SRS-A. This distinguishes these substances

from histamine, bradykinin, and PGF

.LTC

and

LTD

are respectively about 200-fold and 20 000-

fold more potent than histamine in promoting small

airway contraction. In addition, these LTs cause rapid

arteriolar contraction and promote plasma leakage in

postcapillary venules. They also slow the rate of

mucus clearance from the airways of patients with

asthma after the inhalation of antigen and increase

the amount of mucus glycoprotein synthesis in the

airways.

0013With the advent of cloning of various prostanoid

synthetases and their receptors, vast numbers of pros-

tanoids analogs synthesized so far will be retested.

Diverse physiological actions of various prostanoids

will be shortly reevaluated and reclassified, based on

their specific receptors using a specific agonist and

antagonist. For example, inhibition of vasopressin-

induced water reabsorption in kidney or histamine-

induced gastric acid secretion can be explained by

-mediated inhibition of adenylate cyclase. Fur-

thermore, genetic engineering such as prostanoid

receptor knockout mice may be able to clarify a

specific physiological role of PGs and LTs.

Effects of Diet on PG Formation

Polyunsaturated Fatty Acids

0014It was first shown in 1974 that dietary deficiency of

essential fatty acids in animals results in hyperten-

sion, which depends on a high sodium intake, thus

being very similar to renoprival hypertension or

experimental ‘salt sensitive‘ hypertension. This was

later confirmed in 1983, and the blood-pressure

response was attributed to a dietary deficiency of

linoleic acid. However, it would appear unlikely that

this is a cause of human hypertension, since selective

deficiency of essential fatty acids in the human diet is

rare.

PROSTAGLANDINS AND LEUKOTRIENES 4801

0015 A low prevalence of atherosclerosis and a low mor-

tality from myocardial infarction among Greenland

Inuit, despite a diet high in fat and cholesterol, sug-

gested that dietary fish may have some properties that

could prevent coronary artery disease. The Inuit con-

sume 5–10 g daily of the long-chain n-3 polyunsatur-

ated fatty acids EPA (C20; 5n-3) (Figure 2)and

docosahexaenoic acid (C22; 6n-3), which are present

in fish oils. When n-3 fatty acids are included in the

diet, EPA inhibits conversion of linoleic acid and

competes with arachidonic acid for the 2-acyl pos-

ition in membrane phospholipids, reducing plasma

and cellular levels of arachidonic acid. In addition,

EPA competes with arachidonic acid as the substrate

for cyclooxygenase. The platelets produce biologi-

cally inactive TXA

instead of TXA

. However,

PGI

synthesis in endothelial cells is not markedly

inhibited, and any newly synthesized PGI

has the

same potency as PGI

. Thus, a diet abundant in EPA

may inhibit platelet aggregation and cause vascular

dilatation, resulting in blood-pressure reduction. In

fact, a metaanalysis including 1356 subjects from

31 placebo-controlled trials confirmed the blood-

pressure-lowering effects of dietary fish oils. The

hypotensive effect was dose-dependent; there was

little change in blood pressure at doses lower than

3 g per day (corresponding to 250 g of salmon), but

above this, a 0.66 mmHg fall in systolic blood pres-

sure was demonstrated per 1.0-g increase in n-3 poly-

unsaturated fatty acid. The hypotensive effect

appeared greater in patients with hypertension,

hypercholesterolemia, or coronary heart disease.

Mechanisms by which n-3 polyunsaturated fatty

acids may act might be attributed to an attenuated

constrictor responses to vasoactive agents, such as

noradrenaline and angiotensin II, an attenuated sym-

patho-adrenal stimulation and/or modulated pro-

duction or release of nitric oxide from vascular

endothelial cells. However, the safety and long-term

benefits of this treatment have been questioned

because PGE

synthesis is inhibited and replaced

by PEG

from EPA in the fish oils. Since renal

blood flow is dependent on PGE

in renal disease

and during volume contraction, any decrease in

PGE

might result in more severely compromised

renal function.

0016The other merit of dietary fish or fish oil supple-

ments may be its lowering effect on plasma lipid. The

principal effect has been found to be a reduced pro-

duction of triacyglycerols and very-low-density lipo-

protein (VLDL) in the liver. Because VLDL is a

precursor of low-density lipoprotein (LDL), a second-

ary reduction in LDL cholesterol is also seen. Such

conditions are considered to reduce the atherogeni-

city of lipoprotein particles. Futhermore, n-3 fatty

acids have been reported to improve insulin sensitiv-

ity in skeletal muscle, possibly through a decrease in

triacylglycerol accumulation. However, fish oil sup-

plementation to diabetic patients resulted in no

change in glycemic control in one study and an actual

deterioration in glycemic control in another study.

0017Increased intake of polyunsaturated fatty acids has

also been reported to result in reduced gastric acid

secretion and an increase in gastric mucosal protec-

tion. Diets enriched in fish oil or dihomo-g -linolenic

acid also reduce LTB

formation in leucocytes or

monocytes, suggesting a possible role for fish oil

diets in suppressing inflammation in such disorders

as rheumatoid arthritis or systemic lupus erythema-

tosus.

Carbohydrate

0018The increase in urinary excretion of TXB2 associated

with a decreased 6-keto-PGF

has been demon-

strated in diabetic animals and humans. An overpro-

duction of PGE

has also been considered to be one of

the reasons for glomerular hyperfiltration. In fact,

enhanced growth of mesangial cells under high-

glucose conditions can be explained, at least in part,

by a decreased cyclic adenosine monophosphate pro-

duction via EP

, which augments EP

function in

conjunction with the overproduction of PGE

Diabetic pregnancy is associated with growth

disturbances and malformations in the offspring.

Embryonic dysmorphogenesis induced by high con-

centration of glucose is protected by addition of ara-

chidonic acid or PGE

. COX inhibitors such as

indomethacin or aspirin yield embryonic dysmorpho-

gensesis similar to that caused by glucose, indicating

that this disturbance may be partly mediated via

altered metabolism of arachidonic acid.

Proteins

0019Protein intake has profound effect on renal hemody-

namics and excretory function. A high protein intake

has been shown to have deleterious effects on the

kidneys, especially in preexisting renal disease, indi-

cating a rationale for dietary protein restriction to

lessen renal parenchymal damage. However, not all

proteins are equipotent in relation to their renal

COOH

fig0002 Figure 2 Eicosapentaenoic acid (EPA).

4802 PROSTAGLANDINS AND LEUKOTRIENES

effects. A lower glomerular filtration rate and renal

plasma flow, as well as reduced excretion of albumin

and some proteins, have been reported in vegan and

lactovegetarian individuals compared with omnivo-

rous subjects. In fact, acute (more than 80 g) or

chronic loading (more than 1 g per kg of body weight

per day) with animal proteins has resulted in an in-

crease in renal plasma flow and glomerular filtration

associated with a higher clearance of albumin than

that on vegetable protein diets. Vasodilatory PGs such

as PGI

, which may be partly dependent on a rise in

glucagon secretion from the pancreas, have been pro-

posed as a possible mediator of such renal effects of

animal proteins, since the administration of indo-

methacin was found to abolish the renal response to

a meat meal.

Minerals

0020 The isolation and identification of renal PGE

and

PGA

between 1965 and 1967 provided biochemical

support for the renal anitihypertensive-endocrine

function. Numerous studies in humans and animals

thereafter have shown that PGE

has a potent vaso-

dilatory and natriuretic action and hence a pivotal

role in sodium homeostasis. In fact, PGE

adminis-

tration augments renal blood flow and urinary

sodium excretion. In addition, PGE

stimulates renal

renin secretion and inhibits vasopressin-mediated

water reabsorption. During a low sodium intake,

the renin–angiotensin axis is activated by volume

depletion, resulting in antinatiuresis and vasocon-

striction. Renal PGE

synthesis is stimulated by ele-

vated circulating angiotensin II, which then

counteracts the action of angiotensin II, leading to

normalization of renal blood flow, blood pressure,

and sodium excretion (Figure 3). This is the rationale

for the beneficial effects of a low-sodium diet on these

cardiovascular parameters. The same can be said for

diuretic therapy, since the renomedullary synthesis of

PGE

from arachidonic acid is directly stimulated by

furosemide. The natriurietic and antihypertensiv

effects of furosemide are mediated by this newly syn-

thesized PGE

, since both effects are inhibited by

indomethacin. While COX-1 has long been recog-

nized to be involved in normal kidney function,

COX-2 is now seen to have a distinct role. COX-2

has been localized in both the macula densa and the

interstitial cells of the medulla. Chronic sodium de-

privation was found to increase COX-2 levels in the

macula densa, and COX-2-generated prostanoids

may be important mediators of renin production

and tubuloglomerular feedback.

0021 Dietary potassium deficiency leads to hypokalemia

and impairment of maximal urinary concentrating

ability. Since PGE

antagonizes vasopressin-induced

water reabsorption, an increase in renomedullary

PGE

production was postulated to underlie this con-

centrating defect. However, during chronic dietary

potassium depletion secondary to dietary potassium

deprivation in animals, PGE

synthesis by the renal

medulla is markedly reduced, and thus current evi-

dence does not support a role for PGs in hypokalemic

polyuria.

0022Oral calcium supplementation has been reported to

decrease blood pressure in some patients with essen-

tial hypertension and hypertensive rats. However, in

other studies, calcium supplementation produced no

effect on blood pressure in normotensive or hyperten-

sive subjects, Although calcium supplementation has

been shown to increase urinary PGE

excretion in

normotensive women, there was no associated fall

in blood pressure.

Spices

0023Spices have been consumed by many cultures for

thousands of years. In fact, in classical Indian (Ayur-

vedism), Chinese, or Graeco-Arabic systems of medi-

cine, some spice-containing plant materials were used

to prevent or treat some diseases. Some spices have

Sodium restriction

Renin

Angiotensin II PG release

Aldosterone

Sodium retention

Sodium excretion

Blood pressure

Renal blood flow

fig0003Figure 3 Scheme whereby volume depletion secondary to

dietary sodium restriction leads to an increase in PG release

from the renal medulla and resultant physiological actions of

angiotensin II. From Lee JB (1980) Prostaglandins and the

renin–angiotensin axis. Clinical Nephrology 14: 159–163, with

permission.

PROSTAGLANDINS AND LEUKOTRIENES 4803

been shown to inhibit platelet aggregation. These

include onion, garlic, ginger, cloves, omum, cumin,

and turmeric. Extracts from these spices were found

to inhibit platelet COX, allowing less TXA

to be

produced. As COX is inhibited, more substrate (ara-

chidonic acid) becomes available to the lipoxygenase

pathway, as shown by the observation that 12-

HPETE increases in platelets treated with extracts

from ginger, cloves, cumin, and turmeric. However,

onion extracts have been demonstrated to inhibit the

5- or 12-lipoxygenase in platelets. This might at least

partially explain the observation that crude ethanolic

extracts of onion prevented allergen-induced bron-

choconstriction in animals and humans. Ginger,

which is demonstrated to have both antihistaminic

and antioxidant action, also inhibits both the COX

and 5-lipoxygenase pathway. Garlic extracts have

also been demonstrated to inhibit COX activity and

LTC4 formation.

See also: Calcium: Physiology; Fatty Acids: Metabolism;

Dietary Importance; Tr a n s -fatty Acids: Health Effects;

Fish: Dietary Importance of Fish and Shellfish;

Hypertension: Physiology; Nutrition in the Diabetic

Hypertensive; Potassium: Properties and Determination;

Physiology; Renal Function and Disorders: Nutritional

Management of Renal Disorders; Sodium: Physiology