RT Journal Article
SR Electronic
T1 Variability of CYP3A7 Expression in Human Fetal Liver
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 626
OP 635
DO 10.1124/jpet.105.086504
VO 314
IS 2
A1 J. Steven Leeder
A1 Roger Gaedigk
A1 Kenda A. Marcucci
A1 Andrea Gaedigk
A1 Carrie A. Vyhlidal
A1 Bradley P. Schindel
A1 Robin E. Pearce
YR 2005
UL http://jpet.aspetjournals.org/content/314/2/626.abstract
AB Fetal liver CYP3A7 plays an important role in placental estriol synthesis during pregnancy, yet little is known concerning the extent or consequences of variability in expression. The purpose of this investigation was to characterize the variability in CYP3A7 expression using several phenotypic measures in a panel of 54 fetal livers ranging in age from 76 days to 32 weeks gestation. CYP3A7 mRNA expression was measured using quantitative polymerase chain reaction, whereas immunoreactive CYP3A7 was determined using an affinity-purified antipeptide antibody. Variability in catalytic activity was evaluated using testosterone and dehydroepiandrosterone (DHEA) as substrates. Across the entire panel, CYP3A7 was the most abundant CYP3A mRNA species present and varied 634-fold from 151 to 95,700 transcripts/ng total RNA, corrected for 18S ribosomal RNA. CYP3A4 expression was minimal based on mRNA expression (1000-fold lower than CYP3A7) and the ratio of testosterone 2α- (T2αH) to 6β- (T6βH) hydroxylation. T2αH and T6βH were highly correlated (r2 = 0.859), and the correlation increased (r2 = 0.974) in livers with CYP3A5*3/*3 genotypes implying that the same enzyme (CYP3A7) generated both products. Overall, T2αH and DHEA16αH activities varied 175- and 250-fold, respectively. A subset of five samples had extremely low mRNA, protein, and catalytic activity, possibly due to pathology affecting fetal viability (anencephaly, porencephaly). In the remaining samples, T2αH activity varied 6.7-fold (358 ± 142, range 97 to 643 pmol/min/mg) and DHEA16αH activity varied 6.2-fold (8.07 ± 2.87, range 2.41 to 14.9 nmol/min/mg). Observed variability in CYP3A7 activity was not related to CYP3A7*2, and alternative regulatory mechanisms require further investigation. The American Society for Pharmacology and Experimental Therapeutics