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HY Yang, QP Lee, AE Rettie and MR Juchau
Department of Pharmacology, School of Medicine, University of Washington, Seattle 98195.
Expression of functional cytochrome P450 (CYP) isoforms in human embryonic tissues was explored during organogenesis (days 50-60 of gestation) with substrate probes, inhibitor probes, and immunoprobes and by reverse transcription-polymerase chain reaction (PCR), cloning, and sequencing. Evidence was obtained for the presence of relatively high levels of one or more functional CYP3A isoforms in embryonic livers. This was manifested as relatively extensive hydroxylation of (R)-warfarin at carbon 10 and as triacetyloleandomycin-inhibited O- debenzylation of benzyloxyresorufin when human embryonic hepatic microsomal fractions were used as enzyme sources. Immunoblots with anti- CYP3A4 antibody exhibited a strong signal in embryonic hepatic tissues but, in contrast, indicated very low or negligible CYP3A levels in human embryonic lung, kidney, heart, adrenal, and brain tissues. To explore expression of individual members of the CYP3A subfamily in human embryonic hepatic tissues at this early gestational stage, CYP3A cDNA was generated by reverse transcription, amplified by PCR, cloned, and sequenced. Oligonucleotide primers used for PCR were designed to flank target sequences unique to CYP3A but also common to all human CYP3A subfamily members for which GenBank nucleotide sequence information was available (CYP3A3, CYP3A4, CYP3A5, CYP3A5P, and CYP3A7). Sequencing data indicated that plasmids in 58 of 59 recombinant positive colonies contained an insert with a sequence identical to that present in CYP3A7 cDNA and the plasmid of only one colony contained an insert with a sequence identical to that present in CYP3A5 cDNA. No evidence was found for expression of CYP3A3 or CYP3A4. Thus, during organogenesis, human embryonic hepatic tissues express primarily CYP3A7 and are capable of significant CYP3A7-catalyzed xenobiotic monooxygenation during this very early stage of gestation.
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