Ortiz de Montellano Paul R.(Ed.) Cytochrome P450. Structure, Mechanism, and Biochemistry

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Human

and Rat

Liver Cytochromes P450

Table

A.2.

(continued)

627

P450S

Substrate"

Inhibitor^

\>—CH—CH2—NH—C—CHg

CH3

(+/-)

Bufuralor

SCH66712^^96

CH3O

-^^^

Dextromethorphan

Hydrobromide^"^ ^^

c„.o^J>-o

Paroxetine (l\/IBI/Qlf

CYP2E1

Chlorzoxazone

97-99

CH3

4-l\/lethylpyrazole^^9^^^

(CH3)2N—N=0

yV-Nitrosodimethylamine^^^^°^

(CH3CH2)2N-C-SH

Diethyldithiocarbamate^^

^^^ ^^^

CYP3A4

CH3

Testosterone^o^^^^

CH3

Azamulin"^

628 M.A.

Correia

Table A.2. (continued)

P450s

Substrate^

Inhibitor^

CH3^.^-^^OCH3

I >CH3

OHCH3

Erythromycin

116,117

^^3

H3C

CH3

^ H3C' ^O

OH I/CH3

\^^^0C0CH3

6CH3

Troleandomycin

(MBI/QO^i^ ^^^

H3CO2C

Nifedipine'

Gestodene (MBI/S)

Ketoconazole'

A18,48,

115, 122

Human and

Rat

Liver Cytochromes P450

Table A.2. (continued)

629

P450s

Substrate^

Inhibitor^

f<::^=^^^^N-0CH3

V-OCOCHa

Midazolam''

H3C

CH3

Diltiazam (MBI/QI)^

^^e

CYP3A5

Midazolam^ 128,129,131

OCH3

Aflatoxin

630

M.A.

Correia

Table

A.2.

(continued)

P450S

Substrate^ Inhibitor^

CYP3A7

HO3SO

DHEA-Sulfate'

CYP4A11

COOH

Laurie acid

17-0DYA(MBI/S)>

COOH

^^N^^N'°"

~\-

HET0016^^^^^2

10-IDA^^

141

COOH

Human and

Rat

Liver Cytochromes P450

Table A.2. (continued)

631

P450S

Substrate^

Inhibitor^

CYP4F2

COOH

10-UDYA(MBI/Sr

CYP4F12

Arachidonic acid^"^^

OOH

CYP7A1

Cholesterol^

CYP8B1

3-One-4-ene-7a-hydroxycholesterol

632 M.A. Correia

Table A.2. (continued)

Additional literature references are listed in Table A.2.

"Arrow(s) indicate(s) the substrate position(s) oxidized by that particular P450 isoform, enabling the assay of the

corresponding oxidized metabolite(s) as its relatively selective functional probe(s).

*The arrow indicates the inhibitor site that is metabolically activated by that P450 isoform resulting in mechanism-

based inactivation (MBI) of the enzyme that is either irreversible (suicide, S) or quasi-irreversible (QI).

^Inhibitor acts competitively by coordinating to the P450 heme-iron and/or ligation to the protein at the active site.

^2-PMADA, 2-isopropenyl-2-methyladamantane.

^3-PMDIA, 3-isopropenyl-3-methyldiadamantane.

^SCH66712, 5-fluoro-2-[4-[(2-phenyl-1 H-imidazol-5-yl)methyl]-1 -piperazinyl]pyrimidine.

^A metabolic intermediate complex (MIC) observed only with CYP3A4 but not CYPs 3A5 and 3A7.

^Given their —89% sequence similarity, CYP3A4 and CYP3A5 have similar functional and inhibitory profiles.

However, CYP3A5 may be distinguished from CYP3A4 by its higher metabolic ratio of midazolam

'-/4-hydroxyla-

tion, aflatoxin Bl 8,9-epoxidation to 3a-hydroxylation, and alprazolam 4-/1'-hydroxylation, as well as by its inabil-

ity to form a diltiazam-MIC. Mifepristone has also been found to distinguish between the two CYP3A isoforms.

'DHEA-sulfate, dehydroepiandrosterone sulfate.

^17-ODYA, 17-octadecynoic acid. (Ortiz de Montellano, personal communication)

^ETOOl

A^-Hydroxy-A'^'(4-butyl-2-methylphenyl)-formamidine.

^10-IDA, 10-imidazolyldecanoic acid.

'"LTB4, leukotriene B4.

"10-UDYA, 10-undecynoic acid. (Ortiz de Montellano, personal communication)

Table A.3. Rat Liver P450s: Chemical Structures of Diagnostic

Substrate and Inhibitor Probes

P450s Substrate^ Inhibitor^

<^YP1A1 NH-COCH3 H0\

Acetanilide^^^ Rhapontigenin(MBI/S)^^^

(R)-Warfarin^5^6^^i

7-Ethoxyresorufin^ 40,41

(O-Deethylation)

Human and

Rat

Liver Cytochromes P450

Table A.3. (continued)

633

P450S

Substrate^

Inhibitor^

CYP1A2

Caffeine^'

(N'Demethylation)

Galangin (3,5,7-trihydroxyflavoney

f-e,

Theophylline^

CH3O

7-Methoxyresorufin

in40,4i

Furafylline (MBI/S)^

Phenacetin"^ ^^2

(O'Deethylation)

CYPIBI

CH3OH

CH3O

-OCH3

"OCH3

TMS (2,

3', 5'-tetramethoxystilbene)i^4

7-Ethoxyresorufin^

i54^i56

(O-Deethylation)

CYP2A1

9^3 PH

Testosterone^

634

M.A. Correia

Table A.3. (continued)

P450S Substrate^

Inhibitor^

CYP2A2

Testosterone'^^

'^^

CYP2B1

9^3

Testosterone'* Secobarbital (MBI/S)'^^

'^^

\ /"CH2CH2—NH—C—CHCIF

A/-2-P-BPCFA (MBI/S)'68

CH3CH2CH2Cn2CH2

7-Pentoxyresoruf

in'

^^2

y-CH2CH2—NH—C—CHCIF

A/-2-P-NPCFA (IVIBI/S)'68

9-Ethynylphenanthrene (l\/IBI/Sy

,169.

CYP2C6

2ICH3

Progesterone

171,172

CH2

C—H

Pregn-4,20-diene-3-one (l\/IBI/S)'

Human

and

Rat

Liver Cytochromes P450

Table A.3. (continued)

635

P450S

Substrate^

Inhibitor^

(S)-Warfarin^5^6^5i

CYP2C7

Testosterone^

1^2,

i63

(16a-Hydroxylation)

Progesterone^'

^^^

(16a-Hydroxylation)

Sulfaphenazole"^

CYP2C11

CYP2C12

9"3 PH

Testosterone^^^'

^^^

CH3

^"^C-0

Progesterone^^^

COOH

Diclofenac

(l\1BI/S)^

CYP2C13

OSO3H

HOaSO-^

5a-androstane-3a,17pdiol,

3,17-disulfate^^^

Testosterone"^

^^°^^^

(6p'Hydroxylatlon)

636

M.A.

Correia

Table

A.3.

(continued)

P450S

Substrate^

Inhibitor^

CYP2D2

CH3

NHCO—CH^-N(CH2CH3)2

Debrisoquine

(4-Hydroxylationy ^^^

(+/-)

Bufuralol

(T-Hydroxylationy

^^9,

iso

NHCH3

4-Allyloxymethamphetamine(MBI/S)^^^

CYP2E1

Chlorzoxazone"^

^^^

^^2

(6-Hydroxylation)

^H=CH

trans'^

,2-dichloroethylene

(MBl/S)^^^

/V-Nltrosodlmethylamine^

100,

i84,

i89

(N-Demethylation)

DIallylsulfone

(MBI/S)^

186-189

CYP3A2/3A23

Testosterone^'

i^^,

i63,190

CH3

ep-Thiotestosterone

(MBI/S)^-