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Publisher Summary This chapter describes the loss of methylcyclohexyl stereospecificity during cytochrome P-450-dependent monooxygenation. Alicyclic hydroxylation by cytochrome P-450 monooxygenase has been examined using phenobarbital, 3-methylcholanthrene, and β-napthoflavone induced and noninduced rat liver microsomes. In the presence of microsomes, O 2 , NADP + , and NADPH generating system trans-4-methyl-CCNU forms six hydroxyl metabolites. Cis-4-methyl-CCNU undergoes monooxygenation in at least three positions. It is found that during monooxygenation minor metabolites of both trans-4-methyl-CCNU and/or cis-4-methyl-CCNU has been identified showing evidence for the loss of methylcyclohexyl stereospecificity. The identity of these metabolites has been determined by adsorptiv1e and reverse high performance liquid chromatography, and mass spectroscopy. A small percentage of the methyl group during 4 position monooxygenation flips from the trans to cis position or from the cis to trans position. Loss of stereospecificity in the presence of cytochrome P-450 monooxygenase is another chemical modification to which drug may be subjected. This leads to a broad distribution of possible alicyclic ring metabolites with equally broad chemical properties. The isomerization of cis-4-methyl CCNU and trans-4-methyl-CCNU lends support to the idea that a hemolytic hydrogen abstraction is involved in this hydroxylation. |
