Age- and sex-dependent induction of liver microsomal benzo[a]pyrene hydroxylase activity in rats treated with pregnenolone-16 alpha-carbonitrile (PCN).
The present studies were undertaken to resolve conflicting reports on the inducibility of liver microsomal benzo[a]pyrene hydroxylase activity in rats treated with pregnenolone-16 alpha-carbonitrile (PCN). Several studies have shown that treatment of Long Evans rats with PCN causes a 5- to 10-fold induction of benzo[a]pyrene hydroxylase activity, whereas little or no induction occurs in Sprague-Dawley or Wistar rats. Studies with one-month-old-male Long Evans, Sprague-Dawley, Wistar and Holtzman rats failed to reveal an anticipated strain difference in the inducibility of benzo[a]pyrene hydroxylase activity by PCN. Studies with immature and mature male and female Long Evans rats revealed that the inducibility of benzo[a]pyrene hydroxylase activity decreases with age in male but not female rats, i.e., PCN induced benzo[a]Pyrene hydroxylase activity 5- to 8-fold in immature male, immature female and mature female rats but only 2-fold in mature male rats. The age-dependent decrease in inducibility by PCN in male rats coincided with an age-dependent increase (2.4-fold) in the basal activity of benzo[a]pyrene hydroxylase. These sex-dependent developmental changes can be explained by an age-dependent increase in the constitutive levels of the major PCN-inducible form of cytochrome P-450 (cytochrome P-450-PCN) in male but not female rats. Electrophoresis of liver microsomes and studies on the binding of metyrapone to dithionite-reduced cytochrome P-450 provided additional evidence for age- and sex-dependent differences in the levels of microsomal cytochrome P-450-PCN. In addition to reconciling the conflicting literature reports, the age- and sex-dependent differences in cytochrome P-450-PCN levels account, at least in part, for age and sex differences in certain liver microsomal enzyme activities, including benzo[a]pyrene hydroxylase activity.
D000367:Age Factors; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D001579:Benzopyrene Hydroxylase / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D008797:Metyrapone / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D010634:Phenobarbital / Q000494:pharmacology; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012737:Sex Factors
D011285:Pregnenolone Carbonitrile; D008748:Methylcholanthrene; D003577:Cytochrome P-450 Enzyme System; D001579:Benzopyrene Hydroxylase; D001189:Aryl Hydrocarbon Hydroxylases; D010634:Phenobarbital; D008797:Metyrapone