CYP3A4 variant alleles in white individuals with low CYP3A4 enzyme activity.
OBJECTIVE
Our objective was to evaluate the presence of CYP3A4 gene variants in white individuals with 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 in 30 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 or other functionally related genes.
García-Martín
Elena
E
Department of Biochemistry, School of Biological Sciences, University of Extremadura, Badajoz, Spain.
Martínez
Carmen
C
Pizarro
Rosa M
RM
García-Gamito
Francisco J
FJ
Gullsten
Harriet
H
Raunio
Hannu
H
Agúndez
José A G
JA
D000328:Adult; D000483:Alleles; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D003915:Dextromethorphan / Q000378:metabolism / Q000652:urine; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism; D010597:Pharmacogenetics; D044465:White People
D018691:Excitatory Amino Acid Antagonists; D003915:Dextromethorphan; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human