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Sex and species differences in hepatic epoxide hydrolase activities towards cis-and trans-stilbene oxide were examined in common laboratory animals, as well as in monkey and man.In general trans-stilbene oxide was found to be a good substrate for epoxide hydrolase activity in cytosolic fractions, whereas the cis isomer was selectively hydrated by the microsomal fraction (with the exception of man, where the cytosol also hydrated this isomer efficiently). The specific cytosolic epoxide hydrolase activity was highest in mouse, followed by hamster and rabbit. Epoxide hydrolase activity in the crude 'mitochondrial' fraction towards trans-stilbene oxide was also highest in mouse and low in all other species examined. Microsomal epoxide hydrolase activity was highest in monkey, followed by guinea pig, human and rabbit, which all had similar activities. Sex differences were generally small, but where significant, male animals had higher catalytic activities than females of the same species in most cases.Antibodies raised against microsomal epoxide hydrolase purified from rat liver reacted with microsomes from all species investigated, indicating structural conservation of this protein. Antibodies directed towards cytosolic epoxide hydrolase purified from mouse liver reacted only with liver cytosol from mouse and hamster and with the 'mitochondrial' fraction from mouse in immunodiffusion experiments. Immunoblotting also revealed reaction with rat liver cytosol. The cytosolic and 'mitochondrial' epoxide hydrolases in all three mouse strains and in both sexes for each strain were immunochemically identical.The anomalies in human liver epoxide hydrolase activities observed here indicate that no single common laboratory animal is a good model for man with regard to these activities.Mammalian cells are exposed to a large variety of epoxides, including reactive intermediates formed (usually by the cytochrome P-450 system) during the biotransformation of many xenobiotics [l] ; natural products, especially in the plant kingdom [2]; important biosynthetic intermediates, such as squalene oxide and leukotriene A4 [3]; and other endogenous compounds such as cholesterol 5,6-oxide [4]. A number of these epoxides are highly reactive electrophiles and can bind covalently to many nucleophilic sites in biological molecules. Such binding to protein, RNA and DNA is thought to be responsible for many toxic and genotoxic effects, especially in the case of xenobiotics. (For reviews of these considerations see [5, 61.) Thus, the epoxide hydrolases, which convert epoxides to much less reactive dihydrodiols through the addition of water [7], are considered to be important elements of cellular selfdefense. To date, at least four different epoxide hydrolases have been discovered: a microsomal epoxide hydrolase which acts on many epoxide-containing xenobiotics and/or xenobiotic metabolites [7]; another epoxide hydrolase also localized in the endoplasmic reticulum, at least in mammalian liver, which, as far as we know to date, is specific for cho...

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.

Earlier studies have demonstrated that phenol UDP-glucuronosyltransferase (UGT) activity is up-regulated by pregnant mare's serum gonadotropin (PMSG) in rat ovary, but not liver. This phenomenon was investigated in more detail in the present study. Ovaries and livers of immature rats, rats synchronized with respect to their preovulatory and corpus luteal phases by treatment with PMSG, and mature rats hyperstimulated with PMSG were compared. Under all of these conditions, only one immunoreactive band of UGT, shown to be phenol UGT, was detected in the rat ovary. The effects of oestradiol, progesterone and/or human chorionic gonadotropin (hCG) on the level of phenol UGT in immature rat ovary were also examined. Partial up-regulation was caused by progesterone or oestradiol, together with hCG, whereas progesterone or oestradiol alone had no up-regulating effect. Follicle-stimulating hormone also seemed to be required for the up-regulation in ovaries enriched in corpus luteum. The present findings demonstrate that progesterone is involved in the regulation of phenol UGT in rat ovary by gonadotropins. Regulation by both progesterone and oestradiol was dependent on induction of ovulation and steroidogenesis by luteinizing hormone.

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