EFFECTS OF DOXYLAMINE SUCCINATE ON THYROID-HORMONE BALANCE AND ENZYME-INDUCTION IN MICE

The effects of doxylamine (as the succinate salt) on microsomal enzyme activity and serum thyroid hormone levels were examined in B6C3F1 mic e following dietary exposure for 7 or 15 days (0, 40, 375, 750, or 150 0 ppm in diet, expressed as free base doxylamine). In addition, the he patic P450 enzyme inducer sodium phenobarbital (375 ppm, expressed as free acid phenobarbital) was used as a positive control for CYP2B indu ction. Exposure of mise to doxylamine produced dose-related increases in liver weight at both time points. Liver weights were also increased in the phenobarbital-treated mice, Doxylamine treatment caused a dose -dependent increase (up to 2.6-fold) in liver microsomal cytochrome P4 50 in both male and female mice, at both time points. Analyses of the activities of various hepatic microsomal cytochromes P450 indicated th at doxylamine caused a marked induction of CYP2B enzymes. This was dem onstrated by a large increase in the O-dealkylation of 7-pentoxyresoru fin (up to 38-fold) and the 16 beta-hydroxylation of testosterone (up to 6.9-fold), both of which are indicative of CYP2B induction. In addi tion, like phenobarbital, doxylamine treatment resulted in a modest in duction of CYP3A and CYP2A enzymes and approximately a 50% increase in thyroxine-glucuronosyltransferase activity. Doxylamine did not appear to induce P450 enzymes in the CYP1A, CYP2E, or CYP4A enzyme subfamili es. None of the enzyme-inducing effects of doxylamine could be disting uished from those of phenobarbital. These results suggest that doxylam ine is a phenobarbital-type inducer of liver microsomal cytochrome P45 0 in B6C3F1 mice. Exposure to either doxylamine or phenobarbital also resulted in decreases in serum thyroxine (T4) levels (approximately 80 % of control) with compensatory increases in serum thyroid-stimulating hormone levels (approximately 4-fold). No clear changes in serum trii odothyronine levels were apparent, These findings are consistent with the hypothesis that doxylamine increases the activity of those hepatic enzymes involved in T4 metabolism. (C) 1996 Academic Press, Inc.