Sexual patterns of monooxygenase function in the liver of marine teleosts and the regulation of activity by estradiol
Gray, Elisabeth S.
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Sex differences in hepatic microsomal cytochrome P-450 and monooxygenase activities were investigated in the marine teleosts scup (Stenotomus chrysops) and winter flounder (Pseudopleuronectes americanus). Microsomal cytochrome P-450 content per unit proteln was 3-6 tlmes lower in gonadally mature females than males. Ethoxyresorufin O-deethylase (EROD) activity in microsomes from females of both species was less than or equal to activity in males, reflecting sexually differentiated levels of the responsible isozyme, P-450E. Estradiol (E2) 2-hydroxylation, demonstrated here for the first time in teleost microsomes, was measured via 3H20 release from [2- 3H]E2' Microsomal E2 2-hydroxylase activity in scup was P-450-mediated, although not by P-450E, and was 2-fold lower per unit protein in females than in males. Testosterone 6s-hydroxylase and aminopyrine N-demethylase (APDM) activities in scup were not sexually differentiated. In winter flounder microsomes, E2 2-hydroxylase, testosterone 6s-hydroxylase, and APDM activities were all sexually differentiated. These three activities were decreased 2-3 fold per unit protein and increased 2-4 fold per unit P-450 in gonadally mature female winter flounder. Levels of microsomal P-450E and P-450A were quantified by immunoblot. Specific P-450E content was lower in females than in males of both species, but P-450E per nmol P-45O was sexually differentiated only in winter flounder, where it was decreased in females. P-450A per unit protein was not sexually differentiated in either species, and in scup was not differentiated per nmol P-450. However, in winter flounder P-450A per nmol P-450 was five times greater in females than in males. Previously, reconstituted scup P-450A catalyzed both testosterone 6s-hydroxylase and E2 2-hydroxylase activities (Klotz et al., Arch. Biochem. Biophys., 249 (1986): 326). P-450A levels were positlvely correlated to some extent with these two activities and APDM, suggesting co-regulation with or catalysis by P-450A. E2 injections suppressed microsomal monooxygenase activities and P-450E levels per unit protein in gonadally regressed winter flounder. Qualitatively, this change was like the decreased activities in female winter flounder. Other characteristics of the female-type pattern of monooxygenases were not reproduced by E2 treatment. This suggests that E2 could regulate monooxygenase activities in gonadally mature female winter flounder, but indicates that additional factors are also involved. It is speculated that testosterone or 17a,20S-dihydroxyprogesterone, which are elevated in plasma of spawning female teleosts, may also be regulatory. In rats and mice, sex differences in cytochrome P-450 are imparted by pituitary growth hormone and by the male sex steroid testosterone. In teleosts, sex differences in hepatic monooxygenases could be effected by means other than those known to function in mammals.
Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at the Massachusetts Institute of Technology and the Woods Hole Oceanographic Institution May 1988
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