Gender, xenobiotic-metabolizing enzymes

Many differences in overall toxicity between males and females of various species are known (Table 9.1). Although it is not always known whether metabolism is the only or even the most important factor, such differences may be due to gender-related differences in metabolism. Hexobarbital is metabolized faster by male rats thus female rats have longer sleeping times. Parathion is activated to the cholinesterase inhibitor paraoxon more rapidly in female than in male rats, and thus is more toxic to females. Presumably many of the gender-related differences, as with the developmental differences, are related to quantitative or qualitative differences in the isozymes of the xenobiotic-metabolizing enzymes that exist in multiple forms, but this aspect has not been investigated extensively. 

Other Hormones. Pituitary hormones regulate the function of many other endocrine glands, and hypophysectomy in male rats results in a decrease in the activity of xenobiotic metabolizing enzymes. Administration of adrenocorticotropic hormone (ACTH) also results in a decrease of those oxidative enzyme activities that are gender dependent. In contrast, ACTH treatment of female rats causes an increase in aminopyrine /V-dcmcthylasc but no change in other activities. 

Animal studies have demonstrated that some xenobiotics have a greater impact on males, while others more severely affect females. In some instances, testosterone and, in others, estrogens exert stimulating effects on the action of enzymes that metabolize xenobiotics. This research has been little studied in man but is worth considering when one is confronted with the greater sensitivity of one gender to particular foreign chemicals. 

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