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Hodgson E. Modern toxicology [2004].pdf
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PHYSIOLOGICAL EFFECTS

171

thyroxin. In mice, aminopyrine N -demethylase,aniline hydroxylase, and hexobarbital hydroxylase are decreased, whereasp-nitrobenzoicacid reduction is unchanged. In rabbits, hexobarbital hydroxylation is unchanged, whereas aniline hydroxylation andp-nitrobenzoicacid reduction increase. Thyroid hormone can also affect enzymes other than microsomal monooxygenases. For example, liver monoamine oxidase activity is decreased, whereas the activity of the same enzymes in the kidney is increased.

Adrenal Hormones. Removal of adrenal glands from male rats results in a decrease in the activity of hepatic microsomal enzymes, impairing the metabolism of aminopyrine and hexobarbital, but the same operation in females has no effect on their metabolism. Cortisone or prednisolone restores activity to normal levels.

Insulin. The effect of diabetes on xenobiotic metabolism is quite varied and, in this regard,alloxan-induceddiabetes may not be a good model for the natural disease. The in vitro metabolism of hexobarbital and aminopyrine is decreased in alloxandiabetic male rats but is increased in similarly treated females. Aniline hydroxylase is increased in both males and females with alloxan diabetes. The induction of P450 2D1 in diabetes (and in fasting) is believed to be due to the high circulating levels of endogenously generated ketones. Studies of activity of the enzymes mentioned show no gender differences in the mouse; both sexes show an increase. Some phase II reactions, such as glucuronidation, are decreased in diabetic animals. This appears to be due to a lack of UDPGA caused by a decrease in UDPG dehydrogenase, rather than a decrease in transferase activity, and the effect can be reversed by insulin.

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 aminopyrineN -demethylasebut no change in other activities.

9.3.4Pregnancy

Many xenobiotic metabolizing enzyme activities decrease during pregnancy. Catechol O-methyltransferaseand monoamine oxidase decrease, as does glucuronide conjugation. The latter may be related to the increasing levels of progesterone and pregnanediol, both known to be inhibitors of glucuronosyltransferase in vitro. A similar effect on sulfate conjugation has been seen in pregnant rats and guinea pigs. In some species, liver microsomal monooxygenase activity may also decrease during pregnancy, this decrease being accompanied by a concomitant decrease in P450 levels. An increased level of FMO2 is seen in the lung of pregnant rabbits.

9.3.5Disease

Quantitatively, the most important site for xenobiotic metabolism is the liver; thus effects on the liver are likely to be pronounced in the organism’s overall capacity in this regard. At the same time, effects on other organs can have consequences no less