Characterization of the common genetic defect in humans deficient in debrisoquine metabolism

In population studies of individuals given the antihypertensive drug debrisoquine, two distinct phenotypes have been described: extensive metabolizers excrete 10-200 times more of the urinary metabolite 4-hydroxydebrisoquine than poor metabolizers. In family studies the poor-metabolizer phenotype be...

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Bibliographic Details
Published in:	Nature (London) Vol. 331; no. 6155; pp. 442 - 446
Main Authors:	Gonzalez, Frank J, Skodat, Radek C, Kimura, Shioko, Umeno, Morio, Zanger, Ulrich M, Nebert, Daniel W, Gelboin, Harry V, Hardwick, James P, Meyer, Urs A
Format:	Journal Article
Language:	English
Published:	England Nature Publishing Group 04-02-1988
Subjects:	Base Sequence Cloning Cytochrome P-450 CYP2D6 Deoxyribonucleic acid DNA Family studies Genetics Humans Immunoglobulin Heavy Chains - genetics Immunoglobulin Variable Region - genetics Leukemia, Lymphoid - genetics Mammals Medical disorders Medical research Metabolites Mixed Function Oxygenases - deficiency Molecular Sequence Data Population studies Side effects
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Summary:	In population studies of individuals given the antihypertensive drug debrisoquine, two distinct phenotypes have been described: extensive metabolizers excrete 10-200 times more of the urinary metabolite 4-hydroxydebrisoquine than poor metabolizers. In family studies the poor-metabolizer phenotype behaves as an autosomal recessive trait with an incidence between 5% and 10% in the white population of Europe and North America, and extends to the deficient metabolism of more than 20 commonly prescribed drugs. Clinical studies have shown that such individuals are at high risk for the development of adverse side effects from these and probably many other drugs. Here we show that poor metabolizers have negligible amounts of the cytochrome P450 enzyme P450db1. We have cloned the human P450db1 complementary DNA and expressed it in mammalian cell culture. Furthermore, by directly cloning and sequencing cDNAs from several poor-metabolizer livers, we have identified three variant messenger RNAs that are products of mutant genes producing incorrectly spliced db1 pre-mRNA, providing a molecular explanation for one of man's most commonly defective genes (frequency of mutant alleles 35-43%).
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23
ISSN:	0028-0836 1476-4687
DOI:	10.1038/331442a0