title: Identification and functional characterization of eight CYP3A4 protein variants.
abstract: 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.
authors.affiliation: EPIDAUROS Biotechnologie AG, Bernried, Federal Republic of Germany.
authors.forename: R
authors.initials: R
authors.lastname: Eiselt
authors.forename: T L
authors.initials: TL
authors.lastname: Domanski
authors.forename: A
authors.initials: A
authors.lastname: Zibat
authors.forename: R
authors.initials: R
authors.lastname: Mueller
authors.forename: E
authors.initials: E
authors.lastname: Presecan-Siedel
authors.forename: E
authors.initials: E
authors.lastname: Hustert
authors.forename: U M
authors.initials: UM
authors.lastname: Zanger
authors.forename: J
authors.initials: J
authors.lastname: Brockmoller
authors.forename: H P
authors.initials: HP
authors.lastname: Klenk
authors.forename: U A
authors.initials: UA
authors.lastname: Meyer
authors.forename: K K
authors.initials: KK
authors.lastname: Khan
authors.forename: Y A
authors.initials: YA
authors.lastname: He
authors.forename: J R
authors.initials: JR
authors.lastname: Halpert
authors.forename: L
authors.initials: L
authors.lastname: Wojnowski
mesh_terms: D001483:Base Sequence; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D017931:DNA Primers; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D006899:Mixed Function Oxygenases / Q000235:genetics*; D016296:Mutagenesis; D016133:Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; D007527:Isoenzymes; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human