The genetic polymorphism of debrisoquine/sparteine metabolism-molecular mechanisms.
The genetic polymorphism of debrisoquine/sparteine metabolism is one of the best studied examples of a genetic variability in drug response. 5-10% of individuals in Caucasian populations are 'poor metabolizers' of debrisoquine, sparteine and over 20 other drugs. The discovery and the inheritance of deficient debrisoquine/sparteine metabolism are briefly described, followed by a detailed account of the studies leading to the characterization of the deficient reaction and the purification of cytochrome P-450IID1, the target enzyme of this polymorphism. It is demonstrated by immunological methods that deficient debrisoquine hydroxylation is due to the absence of P-450IID1 protein in the livers of poor metabolizers. The cloning and sequencing of the P-450IID1 cDNA and of IID1 related genes are summarized. The P-450IID1 cDNA has subsequently led to the discovery of aberrant splicing of P-450IID1 pre-mRNA as the cause of absent P-450IID1 protein. Finally, the identification of mutant alleles of the P-450IID1 gene (CYP 2D) by restriction fragment length polymorphisms in lymphocyte DNA of poor metabolizers is presented.
Meyer
U A
UA
Department of Pharmacology, Biocenter of the University of Basel, Switzerland.
Skoda
R C
RC
Zanger
U M
UM
D003647:Debrisoquin / Q000378:metabolism*; D006801:Humans; D007546:Isoquinolines / Q000378:metabolism*; D011110:Polymorphism, Genetic; D013034:Sparteine / Q000378:metabolism*
D007546:Isoquinolines; D013034:Sparteine; D003647:Debrisoquin