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  • Title: The in vitro formation of glutathione conjugates with the microsomally activated pulmonary bronchiolar aklylating agent and cytotoxin, 4-ipomeanol.
    Author: Buckpitt AR, Boyd MR.
    Journal: J Pharmacol Exp Ther; 1980 Oct; 215(1):97-103. PubMed ID: 7452496.
    Abstract:
    Using a new high-pressure anion-exchange chromatographic procedure, two radiolabeled conjugates were separated and assayed quantitatively from incubation mixtures containing lung or liver microsomes, NADPH, [3H]5-ipomeanol and glutathione. The same conjugates were obtained also from similar microsomal preparations containing unlabeled 4-ipomeanol, NADPH and [3H]glutathione. The conjugates were not produced in microsomal incubation mixtures containing only [3H]4-ipomeanol and glutathione, or [3H]4-ipomeanol and NADPH, or [3H]glutathione and unlabeled 4-ipomeanol, or in the presence of [3H]glutathione and NADPH alone. Unlike the parent 4-ipomeanol, the conjugates did not have detectable ultraviolet absorbance at 254 nm. Neither of the conjugates arose trough the reduction of 4-ipomeanol to 1,4-ipomeadiol, followed by further metabolism to a metabolite which reacted with glutathione. The total amounts of reactive 4-ipomeanol metabolites generated (estimated by by sum of conjugates plus covalently bound metabolites) were 2 to 3-fold greater in the presence than in the absence of glutathione. Soluble fraction preparations from homogenates of rat lungs or livers did not enhance the corresponding microsome-mediated production of either conjugate, suggesting that glutathione-transferase activities did not play a major role in glutathione conjugate formation with reactive 4-ipomeanol metabolites. The amounts of both conjugates were enhanced greatly in hepatic, but not pulmonary, microsome preparations from animals pretreated with phenobarbital or 3-methylcholanthrene. However, the ratios of the amounts of the two conjugates produced were similar in hepatic and pulmonary microsomal preparations from control rats, or from rats treated with either inducer. These results indicated that the reactive 4-ipomeanol metabolites formed during pulmonary compared to hepatic microsomal metabolism were similar. Moreover, the previously reported enhancement of the hepatic covalent binding and toxicity of 4-ipomeanol caused by pretreatment with 3-methylcholanthrene, but not by phenobarbital, was not likely due to a major change in the kinds or ratios of reactive 4-ipomeanol metabolites produced by hepatic microsomal enzymes after induction with 3-methylcholanthrene compared to phenobarbital.
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