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Pharmacogenetics of CYP3A7 variability in fetal liver
Author(s) -
Leeder J. S.,
Marcucci K. A.,
Gaedigk R.,
Gaedigk A.,
Pearce R. E.
Publication year - 2004
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2003.11.192
Subject(s) - fetus , medicine , endocrinology , cyp3a4 , biology , cytochrome p450 , metabolism , pregnancy , genetics
Neither the extent nor the consequences of variability in drug biotransformation capacity in utero have received extensive attention to date. The purpose of this study was to characterize the variability of CYP3A7 expression in a sample of 50 fetal livers 76d to 32 wk gestation obtained through NICHD‐supported programs (University of Washington Laboratory for Embryology and the University of Maryland Brain and Tissue Bank for Developmental Disorders). Immunoreactive CYP3A7 was determined using an affinity‐purifed anti‐peptide antibody; activity was determined using testosterone, DHEA and dextromethorphan (DM) as substrates. CYP3A4 did not contribute to total activity based on the ratio of testosterone 2α‐ (T2αH) to 6β‐ (T6βH) hydroxylase activities. T2αH and T6βH were highly correlated (r 2 =0.859) and the correlation improved (r 2 =0.974) in livers with CYP3A5*3/*3 genotypes implying that the same enzyme generated both products. T2αH activity varied 175‐fold (330±167, range 3.6 to 643 pmol/min/mg) and DHEA 16αH activity varied 250‐fold (7170±3690, range 59 to 14,900 pmol/min/mg protein; when corrected for immunoreactive CYP3A7 protein, variability was 60‐ and 110‐fold, respectively. DM N ‐demethylation was least variable (173±97, range 17.3 to 513 pmol/min/mg). CYP3A7 activity is highly variable in fetal liver, and may have important consequences for fetal viability. The pharmacogenetic basis of this variability is under investigation. Clinical Pharmacology & Therapeutics (2004) 75 , P51–P51; doi: 10.1016/j.clpt.2003.11.192