Gender differences in drug metabolism regulated by growth hormone

Abstract

Gender differences in drug metabolism in rats have been known for more than 60 years when it was first reported that the much shorter duration of drug action in the male was due to the effects of testicular androgens. More recent studies have demonstrated that this sexual dimorphism in rat drug metabolism results from the differential expression of a possible dozen, or so sex-dependent hepatic forms of cytochrome P450. Moreover, it is the sexually dimorphic plasma profiles of growth hormone, and not androgens, that directly regulate the expression of these individual forms of hepatic cytochrome P450. Male rats secrete growth hormone in an "on-off" episodic rhythm in which interpulse periods contain no detectable levels of the hormone. Growth hormone secretion in the female rat is also pulsatile, but can be characterized as "continuous" since hormone levels are always present in the circulation. It would appear that the duration of the interpulse period is at least one "signal" in the growth hormone profile regulating hepatic expression of the sex-dependent forms of cytochrome P450, and thus establishing the gender differences in drug metabolism. The exaggerated gender differences in rat drug metabolism (i.e. 300-500%) have made it the standard, and understandably an ideal model in which to investigate the mechanisms regulating these dimorphisms. However, it is also possible that these studies have limited value when extrapolated to other species, such as humans, in which the magnitude of the sexual differences are much smaller, and the dimorphism may be reversed (F > M). In this regard, the mouse model, in which the sexual differences (F > M) in drug metabolizing enzyme activities vary by only 40-100%, are also regulated by sex-dependent plasma growth hormone profiles, and may be more representative of the vast majority of outbred species in which only subtle gender differences occur in drug metabolism.