Abstract
The aim of the present study was to investigate whether the mechanism by which pregnenolone-16α-carbonitrile (PCN) protects rats from digitoxin toxicity was dependent on the induction of liver microsomal cytochrome P-450 p and/or the UDP-glucuronosyltransferase active toward digitoxigenin monodigitoxoside (UDP-GT-dt 1). Evidence is presented that suggests troleandomycin is a selective inhibitor of cytochrome P-450 p in vivo, based on the pattern of inhibition observed when zoxazolamine paralysis time and hexobarbital sleeping time were measured in rats treated with different cytochrome P-450 inducers. A single dose of troleandomycin completely reversed the ability of PCN to protect rats from digitoxin toxicity, establishing the importance of cytochrome P-450 p induction in the protective effect of PCN. The postpubertal decline in constitutive cytochrome P-450 p levels in female but not male rats was paralleled by a female-specific, age-dependent decline in the rate of digitoxin sugar cleavage (i.e., digitoxosyl oxidation of digitoxin to 15′-dehydrodigitoxin and digitoxosyl cleavage to digitoxigenin bisdigitoxoside). This resulted in a marked sex difference in the rate of digitoxin sugar cleavage catalyzed by liver microsomes from mature rats (male/female ~ 6). However, no sex difference in digitoxin toxicity was observed in either immature or mature rats. In contrast to cytochrome P-450 p, liver microsomal UDP-GT-dt 1 activity increased dramatically with age in both male and female rats (mature/immature ~ 10). However, no age differences in digitoxin toxicity were observed in rats of either sex. The results indicate that cytochrome P-450 p and UDP-GT-dt 1 can be independently regulated in rat liver and that large changes in the constitutive levels of these microsomal enzymes have no effect on digitoxin toxicity. This suggests that the induction of cytochrome P-450 p and UDP-GT-dt 1 does not fully account for the mechanism by which PCN protects rats from digitoxin toxicity.
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