Alterations in the hepatic glucocorticoid response to mirex treatment.
Corticosterone has been shown to be involved in the regulation of mirex-induced adaptive liver growth. To further investigate the role of corticosterone in this response, plasma corticosterone, hepatic tyrosine aminotransferase (TAT) activity, and hepatic cytosolic binding of glucocorticoids were determined in male Sprague-Dawley rats following a single oral dose of mirex (100 mg/kg body wt). Mirex stimulated a significant elevation in plasma corticosterone levels 12 and 24 hr after dosing; however, hepatic tyrosine aminotransferase activity was not induced above control levels 6, 12, or 24 hr after mirex dosing. Mirex does not appear to directly inhibit the enzyme because tyrosine aminotransferase activity was increased in a dose-dependent manner in both intact and adrenalectomized rats when corticosterone supplements (1-50 mg/kg body wt) were given after mirex dosing. In an effort to explain the lack of hepatic TAT induction, the concentration of cytosolic binding sites for [3H]dexamethasone in intact, adrenalectomized, and adrenalectomized corticosterone-supplemented rats was measured 12, 24, and 48 hr after mirex dosing. There was a significant decrease in the total concentration of cytosolic binding sites for [3H]dexamethasone 12 and 48 hr after mirex dosing in intact rats, 12 and 48 hr after mirex dosing in adrenalectomized rats, and 12 and 24 hr after mirex dosing in adrenalectomized corticosterone-supplemented rats. There was a significant increase in the apparent dissociation constant (Kd) in intact rats dosed with mirex as compared to the oil controls, but there was no difference in Kd after mirex dosing in the adrenalectomized (ADX) rats when compared to the Kd for the oil-dosed control rats. The maximal binding capacity (Bmax) was not significantly different from oil controls after mirex dosing in either intact or ADX rats. The lack of hepatic TAT induction in the presence of increased plasma levels of corticosterone appears to be related to glucocorticoid receptor alterations in the liver of intact rats.
D000315:Adrenalectomy; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003345:Corticosterone / Q000097:blood; D003600:Cytosol / Q000378:metabolism; D003907:Dexamethasone / Q000378:metabolism; D005938:Glucocorticoids / Q000378:metabolism*; D007306:Insecticides / Q000494:pharmacology*; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008917:Mirex / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000378:metabolism*; D014444:Tyrosine Transaminase / Q000378:metabolism
D005938:Glucocorticoids; D007306:Insecticides; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D014444:Tyrosine Transaminase; D003345:Corticosterone; D008917:Mirex