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

Agneta Blanck, Anders åström, Tiiu Hansson, Joseph W. De Pierre, Jan Åke Gustafsson

Research output: Contribution to journalArticle

28 Scopus citations

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-acetylamino-ftuorene (2-AAF) and partial hepatectomy in the resistant hep-atocyte model (RH-raodel). 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 xenobiotk 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-de-ethylation 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 mkro-somal 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.

Original languageEnglish (US)
Pages (from-to)575-582
Number of pages8
JournalCarcinogenesis
Volume7
Issue number4
DOIs
StatePublished - 1986

ASJC Scopus subject areas

  • Cancer Research

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