Loss of sexual differentiation of metabolism of steroids and xenobiotics in nodular hepatic hepatic tissue from male and female Wistar rats treated according to the resistant hepatocyte model

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Abstract
Male and female rats were treated according to the resistant hepatocyte model, i.e. initiation with diethylnitrosaniine (DEN) and selection/promotion with 2-acetylaminofluorene (2-AAF) and partial hepatectomy (PH). Non-initiated controls were either treated with 2-AAF/PH or with PH only. Initiated male controls, where PH was performed, were also included. In livers obtained at PH marked effects of treatment with DEN and/or 2-AAAF on several cytochrome P450-mediated microsomal reactions towards steroid and xenobiotic substrates were observed. Hepatic N, O-sulfation of N-hydroxy 2-acetylaminofluorene (N-OH-2-AAF) was decreased in rats of both sexes in response to 2-AAF treatment at the time of PH. Microsomes prepared from early male nodules, collected 39 days after initiation, exhibited levels of cytochrome P450 similar to that in liver from non-initiated male rats treated with 2-AAF/PH The microsomal content of cytochrome P450 in nodules from both male and female rats, at 8 and 11 months after the start of the experiment respectively, was lower than that of the surrounding liver. No differences in the metabolism of 4-androstene-3,17-dione (androstenedione) were observed in early male nodules compared with 2-AAF/PH-treated controls. Eight months after initiation several sex differentiated hydroxylations of androstenedione (♂>♀) were lower in nodules than in surrounding and control liver from male rats. Female nodules obtained 11 months post-initiation exhibited a markedly lower capacity for 5α-reduction of androstenedione (♂>♀) than the surrounding liver, whereas no significant differences were observed with respect to the different hydroxylation pathways. N,O-Sulfation of N-OH-2-AAF was the only reaction that was markedly decreased in preparations from early male nodules, compared with livers from non-initiated 2-AAF/PH-treated males. Also in late male nodules the sulfotransferase activity was lower than in the surrounding liver. At 11 months, N,O-sulfation in preparations from female rat liver did not reach the detection level. In conclusion, several enzyme activities are markedly less sex differentiated in nodular tissue from male and female rats than in surrounding tissue or in different kinds of control rat liver. These findings indicate that hepatocyte nodules are to some extent withdrawn from the normal endocrine regulation of rat liver.