Hepatic monooxygenase activities in subjects with a genetic defect in drug oxidation.
Microsomes were prepared from surgical wedge biopsy specimens of the livers of 49 patients and from intact liver lobes of 9 kidney transplant donors with the objective of defining interindividual differences in the content and activities of six monooxygenase activities and their relationship to a common genetic defect in drug metabolism known as "debrisoquine polymorphism." Sixty-one patients were phenotyped in vivo with respect to their urinary metabolic ratio of debrisoquine to 4-hydroxydebrisoquine. Forty-seven patients were found to be extensive metabolizers, 12 patients were arbitrarily classified as "intermediate" metabolizers, and only 2 patients were poor metabolizers. The formation of the 4-hydroxy metabolite from debrisoquine in hepatic microsomes from extensive metabolizers was 1.33 +/- 0.437 nmol . mg protein-1 . 15 min-1 (mean +/- SD, n = 9). Microsomes of the 2 poor metabolizers formed 0.13 and 0.18 nmol 4-hydroxydebrisoquine . mg-1 . 15 min-1. Microsomes of intermediate metabolizers produced 0.464 +/- 0.115 (n = 5) of 4-hydroxydebrisoquine and were distinguished from extensive and poor metabolizers. There was no correlation between the capacity for debrisoquine hydroxylation and the total concentration of microsomal cytochrome P450, cytochrome b5, or the activities of nicotinamide adenine dinucleotide phosphate-cytochrome c reductase, aminopyrine-N-demethylase, aryl hydrocarbon hydroxylase, ethoxycoumarin-O-deethylase, aldrin epoxidase, and 2-biphenylhydroxylase. These studies indicate that genetically defective in vivo metabolism of debrisoquine is caused by a deficiency of a monooxygenase reaction in liver microsomes. Moreover, the findings suggest that direct measurement of the debrisoquine oxidation deficiency may allow the identification of heterozygous carriers of the defect. This conclusion remains to be verified by pedigree analysis.
D015660:7-Alkoxycoumarin O-Dealkylase; D000293:Adolescent; D000328:Adult; D000633:Aminopyrine N-Demethylase / Q000378:metabolism; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003573:Cytochrome b Group / Q000378:metabolism; D015786:Cytochromes b5; D003647:Debrisoquin / Q000378:metabolism*; D005260:Female; D006580:Genetic Carrier Screening; D014644:Genetic Variation; D006801:Humans; D007546:Isoquinolines / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009245:NADH Dehydrogenase / Q000378:metabolism; D010084:Oxidation-Reduction; D010105:Oxygenases / Q000172:deficiency* / Q000378:metabolism; D011110:Polymorphism, Genetic
D003573:Cytochrome b Group; D007546:Isoquinolines; D015786:Cytochromes b5; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C019647:aldrin epoxidase; D010105:Oxygenases; D015660:7-Alkoxycoumarin O-Dealkylase; D001189:Aryl Hydrocarbon Hydroxylases; C021775:biphenyl-2-hydroxylase; D000633:Aminopyrine N-Demethylase; D009245:NADH Dehydrogenase; D003647:Debrisoquin