Human embryonic cytochrome P450S: phenoxazone ethers as probes for expression of functional isoforms during organogenesis.
Human embryonic tissues were investigated during the period of organogenesis with a combination of substrate probes, selective inhibitors and immunoprobes in terms of their capacity to express functional P450 isoforms. A series of phenoxazone ethers utilized as substrate probes revealed that human embryonic hepatic, pulmonary, renal, adrenal and cardiac tissues each contained a complement of functional P450 isoforms when analyzed between days 50 and 60 of gestation. Preparations of each of these tissues contained isoforms capable of catalyzing O-demethylation, O-deethylation, O-depentylation and O-debenzylation of the respective phenoxazone ethers. Investigations with chemical inhibitors and inhibitory antibodies as well as comparisons with vector-expressed, human P450 isoforms suggested that isoforms of P450 subfamilies 1A, 2B, 2C or 3A were not major contributors to any of the observed reactions. The P450-dependent reactions studied exhibited several unexpected and unusual characteristics including a preference for NADH over NADPH as the initial electron donor. Results were consistent with the concept that conceptal-specific P450 isoforms participate in the human embryonic O-dealkylation/debenzylation probe reactions investigated.
Lee
Q H
QH
Department of Pediatrics, School of Medicine, University of Washington, Seattle 98195.
Fantel
A G
AG
Juchau
M R
MR
D000911:Antibodies, Monoclonal; D001571:Benzoflavones / Q000494:pharmacology; D001711:Biotransformation; D002248:Carbon Monoxide / Q000494:pharmacology; D019362:Cytochrome P-450 CYP2B1; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000276:immunology / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000187:drug effects / Q000201:enzymology*; D004987:Ethers / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000276:immunology / Q000378:metabolism*; D008797:Metyrapone / Q000494:pharmacology; D009024:Morphogenesis / Q000187:drug effects; D009966:Orphenadrine / Q000494:pharmacology; D010078:Oxazines / Q000494:pharmacology*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D015262:Xenobiotics / Q000494:pharmacology*
D000911:Antibodies, Monoclonal; D001571:Benzoflavones; D065607:Cytochrome P-450 Enzyme Inhibitors; D004987:Ethers; D007527:Isoenzymes; D010078:Oxazines; D015262:Xenobiotics; C020456:phenoxazinone; C011512:alpha-naphthoflavone; D002248:Carbon Monoxide; D003577:Cytochrome P-450 Enzyme System; D009966:Orphenadrine; D010088:Oxidoreductases; D019362:Cytochrome P-450 CYP2B1; D008797:Metyrapone