Two mutant alleles of the human cytochrome P-450dbl gene (P450C2D1) associated with genetically deficient metabolism of debrisoquine and other drugs

Journal Article · Fri Jul 01 00:00:00 EDT 1988 · Proceedings of the National Academy of Sciences of the United States of America; (USA)

DOI:https://doi.org/10.1073/pnas.85.14.5240· OSTI ID:5472909

Skoda, R C; Gonzalez, F L; Demierre, A; Meyer, R A ^[1]

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1. Biocenter of the Univ. of Basel (Switzerland)

The debrisoquine polymorphism is a clinically important genetic defect of drug metabolism affecting 5-10% of individuals in Caucasian populations. It is inherited as an autosomal recessive trait. A full-length cDNA for human cytochrome P-450db1, the deficient enzyme (also designated P450IID1 for P450 family II subfamily D isozyme 1), has recently been cloned. Leukocyte DNA from extensive metabolizers (EMs) or poor metabolizers (PMs) of debrisoquine was examined by Southern analysis. Two polymorphic restriction fragments were associated with the PM phenotype when DNAs from 24 unrelated PM and 29 unrelated EM individuals were probed with P-450db1 cDNA after digestion with Xba I restriction endonuclease and Southern blotting. Seventy-five percent of PMs had either the 44-kb or the 11.5-kb fragment or both. Segregation of these restriction fragment length polymorphisms in the families of six PM probands demonstrated that each of the two fragments is allelic with the 29-kb fragment present in all EM individuals and suggests that they identify two independent mutated alleles of the P-450db1 gene (designated P450C2D1). The Xba I 44-kb fragment and 11.5-kb fragment were in linkage disequilibrium with restriction fragment length polymorphisms generated by four and five additional restriction endonucleases, respectively, which can be used to identify the same mutant alleles for the P-450db1 gene.

• OSTI ID: 5472909
• Journal Information: Proceedings of the National Academy of Sciences of the United States of America; (USA), Vol. 85:14; ISSN 0027-8424
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
CYTOCHROMES
RFLPS
DNA
HYBRIDIZATION
DRUGS
METABOLISM
DNA SEQUENCING
GENES
HEREDITARY DISEASES
HUMAN POPULATIONS
LEUKOCYTES
MUTANTS
PHOSPHORUS 32
BETA DECAY RADIOISOTOPES
BETA-MINUS DECAY RADIOISOTOPES
BIOLOGICAL MATERIALS
BLOOD
BLOOD CELLS
BODY FLUIDS
DAYS LIVING RADIOISOTOPES
DISEASES
ISOTOPES
LIGHT NUCLEI
MATERIALS
NUCLEI
NUCLEIC ACIDS
ODD-ODD NUCLEI
ORGANIC COMPOUNDS
PHOSPHORUS ISOTOPES
PIGMENTS
POPULATIONS
PROTEINS
RADIOISOTOPES
STRUCTURAL CHEMICAL ANALYSIS
550201* - Biochemistry- Tracer Techniques