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Vol. 62, Issue 1, 162-172, July 2002
Department of Pharmaceutics (Y.S.L., K.E.T.), Institute for Public
Health Genetics (A.L.S.D., K.E.T.), and Center for Ecogenetics and
Environmental Health (S.D.Q., F.M.F.), University of Washington,
Seattle, Washington; Department of Pharmaceutical Sciences, St. Jude
Children's Research Hospital, Memphis, Tennessee (J.Z., J.L., E.G.S.);
and McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins
University, Baltimore, Maryland (J.Z.).
We recently demonstrated that a variant allele of CYP3A5
(CYP3A5*3) confers low CYP3A5 expression as a result of
improper mRNA splicing. In this study, we further evaluated the
regulation of CYP3A5 in liver and jejunal mucosa from white
donors. For all tissues, high levels of CYP3A5 protein were strongly
concordant with the presence of a wild-type allele of the
CYP3A5 gene (CYP3A5*1). CYP3A5 represented greater than 50% of total CYP3A content in nearly
all of the livers and jejuna that carried the CYP3A5*1 wild-type allele. Overall, CYP3A5 protein content accounted for 31% of
the variability in hepatic midazolam hydroxylation activity. Improperly
spliced mRNA (SV1-CYP3A5) was found only in tissues containing a CYP3A5*3 allele. Properly spliced
CYP3A5 mRNA (wt-CYP3A5) was detected in
all tissues, but the median wt-CYP3A5 mRNA was 4-fold
higher in CYP3A5*1/*3 livers compared with
CYP3A5*3/*3 livers. Differences in
wt-CYP3A5 and CYP3A4 mRNA content
explained 53 and 51% of the interliver variability in CYP3A5 and
CYP3A4 content, respectively. Hepatic CYP3A4 and CYP3A5 contents were not correlated when all livers were compared. However, for
CYP3A5*1/*3 livers, levels of the two proteins were
strongly correlated (r = 0.93) as were
wt-CYP3A5 and CYP3A4 mRNA
(r = 0.76). These findings suggest that
CYP3A4 and CYP3A5 genes share a common
regulatory pathway for constitutive expression, possibly involving
conserved elements in the 5'-flanking region.
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