Pituitary regulation of cytochrome P-450-mediated metabolism of steroids and xenobiotics in rat liver microsomes

Abstract

In a previous paper we reported on the influence of sex and pituitary hormones on the selection of diethylnitrosamine-initiated, enzyme-altered cells by 0.02% (w/w) 2-acetylaminofluorene (2-AAF) and partial hepatectomy in the resistant hepatocyte model (RH-model). The islands of enzyme-altered cells in this model grew faster in male than in female rat liver and the growth rate was markedly decreased in male rats bearing ectopic pituitary grafts during the 2-AAF selection period. Male rats are also generally more susceptible to 2-AAF carcinogenesis than female rats. In order to investigate whether the sex differentiated response to 2-AAF selection and 2-AAF carcinogenesis might be due to pituitary control of xenobiotic metabolism, as previously shown for rat liver metabolism of steroid hormones, we have studied the influence of age, sex and pituitary hormones on the cytochrome P-450-mediated hydroxylations of 2-AAF and benzo[a]pyrene (B[a]P), O-deethylation of 7-ethoxyresorufin and the metabolism of 4-androstene-3,17-dione (androstenedione) in rat liver microsomes. Microsomes from prepubertal rats had a generally higher capacity to metabolize the xenobiotic compounds whereas the capacity for androstenedione hydroxylation was low. In adult rats pronounced sex differences and a marked influence of pituitary hormones were observed in the microsomal formation of several 2-AAF metabolites as well as in B[a]P and androstenedione metabolism. The results clearly show that at least the oxidative pathways of 2-AAF and B[a]P metabolism are controlled by pituitary hormones in a similar way to the rat liver metabolism of steroids. These data do not, however, provide any explanation for the previously mentioned sex differences in the RH-model or in 2-AAF carcinogenesis. We therefore suggest that the pituitary regulation of other pathways of 2-AAF metabolism must be considered in order to clarify the biochemical background behind sexually differentiated 2-AAF carcinogenesis in rat liver.

Self-augmentation Effect of Male-specific Products on Sexually Differentiated Progesterone Metabolism in Adult Male Rat Liver Microsomes

“…2). 2 As regards another interesting finding obtained from the present study, it has been reported that endogenous COR production in rat adrenal cortex is suppressed by exogenously administrated COR or cortisol in in vivo and in cell culture systems and that this inhibition probably results from the various effects of these steroids, namely inhibiting ACTH secretion from the pituitary, decreasing ACTH sensitivity of adrenal cortex (23), and stimulating the adrenal 5␣-reductase activity metabolizing COR into its 5␣-reduced products (24). However, several recent studies have clearly shown that the two 11␤-OH corticosteroids, COR and cortisol, are of the poorest substrate group for 5␣-reductases of various organs probably including the adrenal cortex itself (19,20,25), and we showed in the present study that COR and 11␤-OH-P, but not 11␣-OH-P, rather stimulated [ 3 H]PROG 5␣-reductase activity of rat liver microsomes (Fig.…”

“…In the microsomes alone, without additions of NADPH and an unlabeled steroid (the second column), only [ H]5␣-reduced metabolites), because such a postpubertal castration is known to induce a partial feminization of liver microsomal steroid metabolisms by repressing the CYP2C11 and CYP3A2 gene expressions and conversely stimulating the 5␣-reductase gene expression (2,17). It should, however, be noted that there were several reports showing similar results to ours, using intact male rats (2,18 dative metabolism, but the latter did not inhibit it. Most interestingly, 3␣-OH-5␣-P and 3␣,11␤-(OH) 2 -5␣-P, compared with PROG, not only showed stronger inhibitory effects on the oxidative metabolism but also conversely stimulated the 5␣-reductive metabolism.…”

“…The male primarily metabolizes various 3-keto-4-ene steroids such as progesterone (PROG), 1 TEST, and 4-AN into the two oxidized products, 16␣-OH (in some cases, 2␣-OH also) and 6␤-OH products, mainly by the respective, malespecific cytochrome P450 subforms (P450s), CYP2C11 and CYP3A2, whereas the female metabolizes them primarily into the 5␣-reduced products by female-predominant 5␣-reductase (1)(2)(3)(4)(5)(6)(7)(8)(9)(10). Expressions of these sexually differentiated enzyme activities are largely regulated at the transcription level under endocrine control, with the secretory pattern of GH playing a major role.…”

Regulation of the expression of the sex‐specific isoforms of cytochrome P‐450 in rat liver

“…The second step in the formation of the carcinogenic metabolite of 2-acetylaminofluorene is the sulfation of hydroxylamine [67 -691. Sulfotransferase activity is higher in male rats than in females [63]. Neonatal, but not adult, castration decreased liver sulfotransferase activity in the adult animals; the carcinogenic effect of 2-acetylaminofluorene was also decreased [63].…”

“…Feminization of the metabolic pattern by neonatal castration decreased the ability of adult male liver microsomes to metabolize benzo(a)pyrene to the level found in the adult female microsomes. Hypophysectomy, a deletion that masculinizes the metabolic pattern, increased the ability of the female microsomes to metabolize benzo(a)pyrene [63]. Hydroxylation of benzo(a)pyrene in male liver is closely related to the content of cytochrome P-450 IICl1, with a correlation coefficient of 0.85 [41].…”