Influence of cytochrome P-450 type on the pattern of conjugation of 7-hydroxycoumarin generated from 7-alkoxycoumarins

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Abstract
1. Pretreatment of rats with phenobarbitone increased hepatic microsomal 7-methoxy-and 7-ethoxy-coumarin O-dealkylase activities. Pretreatment with β-naphthoflavone increased only the 7-ethoxycoumarin O-dealkylase activity. 2. The addition of metyrapone in vitro inhibited the O-dealkylations to different extents. Similar results were obtained with diphenyloxazole and ethanol. 3. These results are taken to indicate that different forms of cytochrome P-450 are involved in the O-dealkylation of these two substrates. 4. The pattern of metabolism (Phase I and Phase II) of each alkoxycoumarin in rat isolated hepatocytes was very similar. The sulphate conjugate was the major metabolite produced, the amount of which approached a plateau as the rate of O-dealkylation increased. 5. It is concluded that the type of cytochrome P-450 involved in the initial Phase I metabolism does not influence the subsequent pattern of conjugation.