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Vol. 59, Issue 2, 386-392, February 2001
Department of Pharmacology and Toxicology, University of Texas
Medical Branch, Galveston, Texas (T.L.D., J.R.H.); and the Center for
Nutrition and Toxicology, Department of Biosciences at NOVUM,
Karolinska Institute, Huddinge, Sweden (C.F., P.G.Z.)
The RACE amplification technology was used on a novel CYP3A-like exon 1 sequence detected during the reverse transcriptase/polymerase chain
reaction analysis of human CYP3A gene expression. This
resulted in the identification of cDNAs encompassing the complete
coding sequence of a new member of the CYP3A gene
subfamily, CYP3A43. Interestingly, the majority of the
cDNAs identified were characterized by alternative splicing events such
as exon skipping and complete or partial intron inclusion.
CYP3A43 expression was detected in liver, kidney,
pancreas, and prostate. The amino acid sequence is 75% identical to
that of CYP3A4 and CYP3A5 and 71% identical to CYP3A7. CYP3A43 differs
from CYP3A4 at six amino acid residues, found within the putative
substrate recognition sites of CYP3A4, that are known to be
determinants of substrate selectivity. The N terminus of CYP3A43 was
modified for efficient expression of the protein in Escherichia
coli, and a 6X histidine tag was added at the C terminus to
facilitate purification. CYP3A43 gave a reduced carbon monoxide
difference spectra with an absorbance maximum at 450 nm. The level of
heterologous expression was significantly lower than that observed for
CYP3A4 and CYP3A5. Immunoblot analyses revealed that CYP3A43 comigrates
with CYP3A4 in polyacrylamide gel electrophoresis but does separate
from CYP3A5. Monooxygenase assays were performed under a variety of
conditions, several of which yielded reproducible, albeit low,
testosterone hydroxylase activity. The findings from this study
demonstrate that there is a novel CYP3A member expressed in human
tissues, although its relative contribution to drug metabolism has yet
to be ascertained.
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