Identification and functional characterization of eight CYP3A4 protein variants.
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.
Eiselt
R
R
EPIDAUROS Biotechnologie AG, Bernried, Federal Republic of Germany.
Domanski
T L
TL
Zibat
A
A
Mueller
R
R
Presecan-Siedel
E
E
Hustert
E
E
Zanger
U M
UM
Brockmoller
J
J
Klenk
H P
HP
Meyer
U A
UA
Khan
K K
KK
He
Y A
YA
Halpert
J R
JR
Wojnowski
L
L
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
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