ENDOGENOUS REGULATORS OF DRUG METABOLISM

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The levels of hepatic drug metabolizing enzymes are affected by nutritional, environmental, genetic and hormonal factors. In the case of the rat, the animal's sex can have a profound effect on the activities of hepatic monooxygenases, as male rats metabolize drugs at a rate 3 to 5 times faster than female rats. While early studies revealed that testicular androgens were the endogenous agents responsible for inducing the increased activities of the hepatic enzymes, more recent evidence has shown that it is the pattern of growth hormone (GH) secretion, regulated by androgens, that controls the sexual dimorphisms in rat hepatic monooxygenases. Using selective GH deficient rats infused with various circulating patterns of rat GH, we propose to identify the "signalling" elements in the ultradian GH profile that regulate, pre- and/or posttranslationally, the expression of the different forms of P450. In addition, we plan to identify other possible hormonal factors, and determine how they, along with GH, regulate the expression of hepatic forms of P450, as well as modulate the effects of exogenous inducers. At the cellular level, we propose to investigate how the GH receptor, the transducer of GH action, recognizes and discriminates between the different signalling elements in the sexually dimorphic profiles of circulating GH. The exaggerated sex differences in hepatic monooxygenases an plasma GH profiles in the rat are unique, and not representative of what is found in other species. It is for this reason that we have also chosen to examine the effects of hormonal regulators in the mouse. The much less pronounced sex differences in murine drug metabolism and plasma GH rhythms are more representative of other species, including humans. Moreover, the injected regimen of GH that stimulates drug metabolism in the rat, suppresses it in the mouse, and vice versa. Thus, mechanisms that regulate expression of murine P450s may have more universal application, including human health benefits (i.e., controlling drug toxicities) than that found in rats. Although much less is known about the P450-composition of mouse liver than rat liver, both animal models can produce important information. From rat studies, we can learn, at a molecular level, how the secretory pattern of a hormone can regulate both the expression and repression of specific forms of P450. Although less definitive, the mouse studies may at least establish an alternative mechanism by which hormones regulate the expression of hepatic monooxygenases; a mechanism that nay be more characteristic of the human condition.