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Deacetylclivorine: A Gender-Selective Metabolite of Clivorine Formed in Female Sprague-Dawley Rat Liver Microsomes

Department of Pharmacology, the Chinese University of Hong Kong, Hong Kong, SAR (G.L., J.T., X.Q.L., Y.J.); and Center for Developmental Pharmacology and Toxicology, Seattle Children's Hospital Research Institute, Division of Gastroenterology, Department of Pediatrics, University of Washington, Seattle, Washington (J.Z.)

Clivorine, a naturally occurring pyrrolizidine alkaloid, causes liver toxicity via its metabolic activation to generate toxic metabolite (pyrrolic ester). Female Sprague-Dawley (SD) rats are reported to be less susceptible to clivorine intoxication than male SD rats. However, the biochemical mechanism causing such gender difference is largely unknown. The present study investigated hepatic microsomal metabolism of clivorine in female rats to delineate the mechanism of the gender difference. Two pathways, which directly metabolize clivorine, were observed. First, the metabolic activation to produce the toxic pyrrolic ester followed by formations of bound pyrroles, dehydroretronecine, 7-glutathionyldehydroretronecine, and clivoric acid were found in female rats, and CYP3A1/2 isozymes were identified to catalyze the metabolic activation. Compared with male rats (21%), the metabolic activation in female rats was significantly lower (4%) possibly because of significantly lower CYP3A1/2 levels expressed in female rats. Second, a direct hydrolysis to generate the novel female rat-specific metabolite deacetylclivorine was shown as the predominant pathway (16% clivorine metabolism) in female rat liver microsomes and was determined to be mediated by microsomal hydrolase A. Furthermore, when the metabolic activation was completely inhibited by ketoconazole, the amount of deacetylclivorine formed in a 1-h incubation significantly increased from 19.44 ± 3.00 to 54.87 ± 9.30 nmol/mg protein, suggesting that the two pathways compete with each other. Therefore, the lower susceptibility of female SD rats to clivorine intoxication is suggested to be caused by the significantly higher extent of the direct hydrolysis and a lower degree of the metabolic activation.

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