Arch Biochem Biophys. 1997 Oct 1;346(1):161-9.  

Progesterone and testosterone hydroxylation by cytochromes P450 2C19, 2C9, and
3A4 in human liver microsomes.

Yamazaki H, Shimada T.

Osaka Prefectural Institute of Public Health, Nakamichi, Japan.

Roles of human cytochrome P450 (P450 or CYP) 2C9, 2C19, and 3A4 in the oxidation
of progesterone and testosterone were studied in recombinant P450 enzymes and in
human liver microsomes. In vitro inhibition experiments showed that progesterone
and its 17alpha- and 21-hydroxylated metabolites and 11-deoxycortisol suppressed
the CYP2C19-dependent R-warfarin 7-hydroxylation activities, with progesterone
being the most active. These steroid chemicals also inhibited CYP2C9-dependent
S-warfarin 7-hydroxylation activities though lesser extents seen with those in
CYP2C19 enzyme. Progesterone was found to be a competitive inhibitor of CYP2C19
and CYP2C9 in human liver microsomes. Recombinant CYP2C19 catalyzed progesterone
to form 21-hydroxyprogesterone as a major product and 16alpha- and
17alpha-hydroxyprogesterone as minor products. CYP2C9 also had progesterone
21-hydroxylation activities, although the activities were lower than those
catalyzed by CYP2C19. Vmax/Km ratios for the progesterone 21-hydroxylation
activity of CYP2C19 were determined to be 13- and 32-fold higher than those of
CYP2C9 and 3A4, respectively. CYP3A4 oxidized progesterone to form 16alpha-,
6beta-, and 2beta-hydroxyprogesterone as major products and
21-hydroxyprogesterone as a minor product, but did not produce detectable levels
of 17alpha-hydroxyprogesterone. Immunoinhibition experiments suggested that
anti-CYP2C9 (which inhibits both CYP2C9 and CYP2C19 catalytic activities)
suppressed the progesterone 21-hydroxylation activities catalyzed by liver
microsomes of humans and monkeys and that anti-CYP2C11 inhibited the
progesterone 21-hydroxylation activities catalyzed by liver microsomes of male
rats. CYP2C19 was also found to oxidize testosterone at 17-position to form
androstenedione. Androstenedione formation catalyzed by liver microsomes of
humans and monkeys and of male rats was suppressed by anti-CYP2C9 and
anti-CYP2C11, respectively. These results suggest that CYP2C19 plays important
roles in the oxidation of progesterone and testosterone in human liver
microsomes, although the physiological significance of these metabolic pathways
remains unclear. CYP2C9 may have some, but lesser extent than those by CYP2C19,
of the catalytic roles for the metabolism of progesterone and testosterone by
human liver microsomes.

PMID: 9328296 [PubMed - indexed for MEDLINE]