Drug Disposition Overview - Pharmacology and at UCSD

BIOM/PHAR 255 Winter 2013 Halpert - Jan. 17, 2013
Types of P450 Reactions
1. Hydroxylation of aliphatic or aromatic carbons
2. Epoxidation of a double bond
3. Heteroatom (S-, N-) oxygenation and N-hydroxyl
4. Heteroatom (O-, S-, N-) dealkylation
5. Oxidative group transfer
6. Cleavage of esters
7. Dehydrogenation
P450 oxidation reactions
Epoxidation (arene oxide formation)
benzo[a]pyrene
N-, O- and S-dealkylation
O
H3 C CH3 N
CH3CH2 C C CH2CH CH3 methadone
O
benzo[a]pyrene-7,8-epoxide
H3C H
O N
CH3 CH2 C C CH2CH CH3 +
H C
H
O
6 of 22
P450 reactions: oxidation at
C
aliphatic hydroxylation
H 3 C
CH 3CH 2
O
CH2 CH2 CH2 CH3 pentobarbital
aromatic hydroxylation
CH 3CH 2
O
phenobarbital
N
NH ONa
O
NH ONa
O
N
HO
H 3C
CH 3 CH 2
P450 nomenclature
Based on sequence identity:
O
CH
OH
CH 3 CH 2
CH 2
N
O
CH2 CH3 NH ONa
O
NH ONa
MELSVLLLLALLTGLLLLMARGHPKAYGHLPPGPRP…
MEFSLLLLLAFLAGLLLLLFRGHPKAHGRLPPGPSP…
Family: ≥ 40% sequence identity.
for example: CYP1, CYP2
Subfamily: 40% - 55% sequence identity.
for example: CYP2A, CYP2B
Within subfamily: ≥ 55% sequence identity.
for example: CYP2B1, CYP2B4
O
N