Identification and functional characterization of eight CYP3A4 protein variants.
Eiselt R,
Domanski TL,
Zibat A,
Mueller R,
Presecan-Siedel E,
Hustert E,
Zanger UM,
Brockmoller J,
Klenk HP,
Meyer UA,
Khan KK,
He YA,
Halpert JR,
Wojnowski L.
EPIDAUROS Biotechnologie AG, Bernried, Federal Republic of Germany.
The genetic component of the inter-individual variability in CYP3A4 activity has been estimated to be between 60% and 90%, but the underlying genetic factors remain largely unknown. A study of 213 Middle and Western European DNA samples resulted in the identification of 18 new CYP3A4 variants, including eight protein variants. A total of 7.5% of the population studied was found to be heterozygous for one of these variants. In a bacterial heterologous expression system, two mutants, R130Q and P416L, did not result in detectable P450 holoprotein. One mutant, T363M, expressed at significantly lower levels than wild-type CYP3A4. G56D, V170I, D174H and M445T were not significantly different when compared with wild-type CYP3A4 in expression or steroid hydroxylase activity. L373F displayed a significantly altered testosterone metabolite profile and a four-fold increase in the Km value for 1'-OH midazolam formation. The results suggest a limited contribution of CYP3A4 protein variants to the inter-individual variability of CYP3A4 activity in Caucasians. Some variants may, however, play a role in the atypical response to drugs or altered sensitivity to carcinogens.
PMID: 11470997 [PubMed - indexed for MEDLINE]