POLYMORPHIC DRUG OXIDATION--THE HUMAN AND RAT DEBRISOQUINE 4-HYDROXYLASE GENES

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Human polymorphic drug oxidation has been recognized for over 30 years. The most extensively studied is the debrisoquine 4- hydroxylase polymorphism in which 6% to 8% of the Caucasian population in Europe and North America cannot metabolize this drug. Studies in our lab and others confirmed that this polymorphism is due to a cytochrome P-450. We have isolated and produced antibody against the rat debrisoquine 4-hydroxylase (db1) and this antibody was used to obtain the rat and human cDNA clones. These were sequenced and, by comparison to the known P-450 sequences and db1, were found to constitute a separate P-450 gene subfamily. Gene cloning revealed that at least four active genes related to db1 exist and are expressed in rat; only one of these genes may have debrisoquine hydroxylase activity. In contrast, in humans, only one active gene and pseudogene exist. Cloning and sequencing of genes from human livers that do not possess the db1 protein revealed the presence of mutant genes. Three mutant genes were characterized that produce incorrectly spliced mRNA. The db1 probe may be useful for analysis and detection of mutant genes in human populations.