Identification and functional characterization of eight CYP3A4 protein variants

• Published in: Pharmacogenetics (London) Vol. 11; no. 5; p. 447
• Main Authors: Eiselt, R, Domanski, T L, Zibat, A, Mueller, R, Presecan-Siedel, E, Hustert, E, Zanger, U M, Brockmoller, J, Klenk, H P, Meyer, U A, Khan, K K, He, Y A, Halpert, J R, Wojnowski, L
• Format: Journal Article
• Language: English
• Published: England 01.07.2001
• Subjects: Base Sequence; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System - genetics; DNA Primers; Humans; Isoenzymes - genetics; Mixed Function Oxygenases - genetics; Mutagenesis; Polymerase Chain Reaction
• ISSN: 0960-314X
• DOI: 10.1097/00008571-200107000-00008

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.