Cytochrome P-450-dependent biotransformation of 2-acetylaminofluorene in cell-free preparations of human embryonic hepatic, adrenal, renal, pulmonary, and cardiac tissues.
Human embryonic hepatic, renal, adrenal, pulmonary, and cardiac tissues (gestational age = 50-60 days) were probed for functional P-450 isoforms with 2-acetylaminofluorene (AAF) in cell-free preparations. Each of these tissues exhibited P-450-dependent hydroxylation at several positions on the AAF molecule, although activities in renal, pulmonary, and particularly cardiac preparations were generally low. N-hydroxylation activities were marginal to undetectable in all five tissues, but 7-hydroxylation was detectable in each tissue. Highest aromatic ring-hydroxylation activities were observed in hepatic tissues, and adrenal tissues also exhibited relatively high activities for ring-hydroxylation, particularly at carbon-7. The 9-hydroxylated AAF metabolite (9-OH-AAF) was the predominant metabolite for all human embryonic tissues, but generation via catalysis by P-450 isoforms appeared to be minimal/negligible. Activity profiles for human embryonic tissues (days 50-60 of gestation) were compared with those of 12 separate, vector-expressed human P-450 isoforms, with those of human fetal tissues (days 72-140 days of gestation), with those of various rodent embryonic tissues, and with those of adult rhesus monkey and adult rat tissues preexposed to inducing agents. These analyses suggested that each of the human embryonic tissues studied expresses functional, xenobiotic-biotransforming P-450 isoforms, but contrasted with previous investigations with phenoxazone ethers as functional P-450 probes. Resolution of these apparent differences will require further research. Early prenatal expression of functional P-450 isoforms in organogenesis-stage human embryonic tissues has important implications for our understanding and predicting of teratogenic/embryotoxic and other biologic effects of exposures to drugs and other environmental chemicals during human pregnancy.
Namkung
M J
MJ
Department of Pharmacology, School of Medicine, University of Washington, Seattle 98195.
Yang
H L
HL
Juchau
M R
MR
D015073:2-Acetylaminofluorene / Q000493:pharmacokinetics*; D000311:Adrenal Glands / Q000196:embryology / Q000201:enzymology / Q000378:metabolism; D001711:Biotransformation; D002474:Cell-Free System / Q000201:enzymology / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D006321:Heart / Q000196:embryology; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000196:embryology / Q000201:enzymology / Q000378:metabolism; D008099:Liver / Q000196:embryology / Q000201:enzymology / Q000378:metabolism; D008168:Lung / Q000196:embryology / Q000201:enzymology / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism; D010084:Oxidation-Reduction; D011247:Pregnancy
D003577:Cytochrome P-450 Enzyme System; D015073:2-Acetylaminofluorene