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CYP3A4 variant alleles in white individuals with low CYP3A4 enzyme activity
Author(s) -
GarcíaMartín Elena,
Martínez Carmen,
Pizarro Rosa M.,
GarcíaGamito Francisco J.,
Gullsten Harriet,
Raunio Hannu,
Agúndez José A. G.
Publication year - 2002
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1067/mcp.2002.121371
Subject(s) - cyp3a4 , allele , biology , loss of heterozygosity , genetics , gene , population , allele frequency , enzyme , biochemistry , medicine , cytochrome p450 , environmental health
Objective Our objective was to evaluate the presence of CYP3A4 gene variants in white individualswith low CYP3A4 enzyme activity. Methods Persons with extremely low enzyme activity, either in vitro or in vivo, were selected in a panel of 97 healthy subjects. Genetic analyses for CYP3A4 variant alleles present in white subjects, including CYP3A4*1B, CYP3A4*2, CYP3A4*4, CYP3A4*5, CYP3A4*6, CYP3A4*8, CYP3A4*11, CYP3A4*12 , and CYP3A4*13 , were performed on genomic deoxyribonucleic acid from these subjects by amplification‐restriction and sequencing. Results With the exception of CYP3A4*1B , none of the variant alleles analyzed were present in30 genes from persons with extremely low enzyme activity. CYP3A4*1B was present in the population studied with an allele frequency of 5.5%. Nevertheless, the presence of CYP3A4*1B does not correlate with low enzyme activity, either in vivo or in vitro, in either heterozygosity or homozygosity. CYP3A4*2 was not identified in 290 genes from Spanish persons or in 70 genes from Finnish persons. Conclusions Although the genetic component of the interindividual variability of CYP3A4 enzyme activity seems to be high, our findings do not support a key role for the variant alleles analyzed on the majority of white persons with low CYP3A4 activity. This suggests the occurrence of as yet unknown mutations that affect CYP3A4 orother functionally related genes. Clinical Pharmacology & Therapeutics (2002) 71 , 196–204; doi: 10.1067/mcp.2002.121371