Life Sci. 2000;67(2):175-84.  

Identification of human cytochrome P450 isoforms involved in the 7-hydroxylation
of chlorpromazine by human liver microsomes.

Yoshii K, Kobayashi K, Tsumuji M, Tani M, Shimada N, Chiba K.

Laboratory of Biochemical Pharmacology and Toxicology, Faculty of Pharmaceutical
Sciences, Chiba University, Japan.

Studies to identify the cytochrome P450 (CYP) isoform(s) involved in
chlorpromazine 7-hydroxylation were performed using human liver microsomes and
cDNA-expressed human CYPs. The kinetics of chlorpromazine 7-hydroxylation in
human liver microsomes showed a simple Michaelis-Menten behavior. The apparent
Km and Vmax values were 3.4+/-1.0 microM and 200.5+/-83.7 pmol/min/mg,
respectively. The chlorpromazine 7-hydroxylase activity in human liver
microsomes showed good correlations with desipramine 2-hydroxylase activity (r =
0.763, p < 0.05), a marker activity for CYP2D6, and phenacetin O-deethylase
activity (r = 0.638, p < 0.05), a marker activity for CYP1A2. Quinidine (an
inhibitor of CYP2D6) completely inhibited while alpha-naphthoflavone (an
inhibitor of CYP1A2) marginally inhibited the chlorpromazine 7-hydroxylase
activity in a human liver microsomal sample showing high CYP2D6 activity. On the
other hand, alpha-naphthoflavone inhibited the chlorpromazine 7-hydroxylase
activity to 55-65% of control in a human liver microsomal sample showing low
CYP2D6 activity. Among eleven cDNA-expressed CYPs studied, CYP2D6 and CYP1A2
exhibited significant activity for the chlorpromazine 7-hydroxylation. The Km
values for the chlorpromazine 7-hydroxylation of both cDNA-expressed CYP2D6 and
CYP1A2 were in agreement with the Km values of human liver microsomes. These
results suggest that chlorpromazine 7-hydroxylation is catalyzed mainly by
CYP2D6 and partially by CYP1A2.

PMID: 10901285 [PubMed - indexed for MEDLINE]