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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION
Section of Developmental Pharmacology and Experimental Therapeutics, Division of Pediatric Pharmacology and Medical Toxicology, Department of Pediatrics, Children's Mercy Hospital and Clinics, Kansas City, Missouri
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 2
- (T2H) to 6
- (T6H) hydroxylation. T2H and T6H 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, T2H and DHEA16H 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, T2H activity varied 6.7-fold (358 ± 142, range 97 to 643 pmol/min/mg) and DHEA16H 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.
Address correspondence to: Dr. J. Steven Leeder, Section of Developmental Pharmacology and Experimental Therapeutics, Children's Mercy Hospital and Clinics, 2401 Gillham Road, Kansas City, MO 64108. E-mail: sleeder{at}cmh.edu
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