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Effects of Neonatal and Adult Castration on the in Vitro Metabolism of Steroids and Xenobiotics in Rat Liver¹

Department of Medical Nutrition, Karolinska Institutet, Huddinge University Hospital F69, S-141 86 Huddinge [A. B., T. H.], and Department of Biochemistry, Arrhenius Laboratory, University of Stockholm, S-106 91 Stockholm [A. A.], Sweden

Previous studies in our laboratory have shown that the sex-differentiated metabolism of 4-androstene-3,17-dione and of several other steroid hormones in adult rat liver is "feminized" following neonatal castration of male rats, due to an influence via the hypothalamo-pituitary-liver axis. The metabolism of many xenobiotics is also sex differentiated, and an important question is whether endocrine ablations might alter hepatic carcinogen metabolism in a way explaining, for example, the decreased tendency of castrated male rats [Y. C. Toh, In: Shanmagarathnam et al. (eds.), Liver Cancer, Cancer Problems in Asian Countries, Proceedings of the Second Asian Cancer Conference, pp. 167–171. Singapore: Singapore Cancer Society, 1976] to form liver tumors following 2-acetylaminofluorene treatment. The results presented in this paper clearly show that neonatal castration of male rats, much more efficiently than adult castration, feminizes the cytochrome P-450-dependent, sex-differentiated, liver microsomal formation of 7-hydroxy-2-acetylaminofluorene, 9-hydroxy-2-acetylaminofluorene, 5-hydroxy-2-acetylaminofluorene, 1-hydroxy-2-acetylaminofluorene, and N-hydroxy-2-acetylaminofluorene from 2-acetylaminofluorene as well as the total microsomal formation of benzo(a)pyrene metabolites ( > ). O-Deethylation of 7-ethoxyresorufin was neither sex differentiated nor affected by castration. The capacity for in vitro sulfation of N-hydroxy-2-acetylaminofluorene in the postmicrosomal supernatant, markedly sex differentiated in the rat ( > ), was completely feminized by neonatal but not by adult castration. The results suggest that the influence of endocrine ablations on chemical carcinogenesis in rat liver might be mediated via the hypothalamo-pituitary regulation of certain pathways of hepatic xenobiotic metabolism.

¹ This study was supported by grants from the Swedish Medical Research Council (No. 13X-2819), from Cancerföreningen i Stockholm, from Söderbergs Stiftelse, and from the Robert Lundbergs Minnesfond.

² To whom requests for reprints should be addressed.

Received 11/26/85. Revised 5/ 6/86. Accepted 5/14/86.

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