Catalytic roles of rat and human cytochrome P450 2A enzymes in testosterone 7 alpha- and coumarin 7-hydroxylations.
Differences in the catalytic roles of rat and human cytochrome P450 2A enzymes in testosterone 7 alpha- and coumarin 7-hydroxylase activities were examined. Liver microsomes from 18 human samples catalyzed coumarin 7-hydroxylation at a mean rate of about 60 pmol/min/nmol P450, but did not show any measurable activity for testosterone 7 alpha-hydroxylation. In rats, both activities were found to be developmentally regulated; 3-week-old rats had the highest activities for these two reactions. Anti-P450 2A1 antibodies and methoxsalen, a potent inhibitor of P450 2A-dependent monooxygenase activities in several animal species, inhibited almost completely both testosterone 7 alpha- and coumarin 7-hydroxylations catalyzed by liver microsomes prepared from 3-week-old male rats. Interestingly, although Km values for coumarin 7-hydroxylation activities in liver microsomes from 3-week-old rats were not different from those of adult humans, the Vmax value in rats was only 1/30 of that obtained in 18 human samples. Thus, the present results support the view that marked differences exist in the catalytic roles of rat and human P450 2A enzymes, which, in turn, may sometimes cause species-related differences in susceptibilities toward drug actions and toxicities.
Yamazaki
H
H
Osaka Prefectural Institute of Public Health, Japan.
Mimura
M
M
Sugahara
C
C
Shimada
T
T
D000375:Aging; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D065637:Cytochrome P-450 CYP2A6; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D006801:Humans; D006915:Hydroxytestosterones / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013250:Steroid Hydroxylases / Q000378:metabolism*
D006915:Hydroxytestosterones; C032278:4,17 beta-dihydroxy-4-androstene-3-one; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; D065637:Cytochrome P-450 CYP2A6; C022657:steroid hormone 6-beta-hydroxylase; C029009:steroid hormone 7-alpha-hydroxylase