Biotransformation of carcinogenic arylamines and arylamides by human placenta.
Placental biotransformation reactions may modulate the effect a xenobiotic has on the developing fetus. However, in spite of the critical role the placenta plays in supporting fetal life, little is known about the pharmacology and toxicology of the human placenta. Our laboratory has previously characterized the N-acetylation activity of the human term placenta. This activity is predominantly attributable to the NAT1 form of arylamine N-acetyltransferase (NAT). Although acetylation is generally thought to be a detoxifying reaction, both N-acetylation and deacetylation reactions play an important role in the activation of carcinogenic arylamines to their reactive and toxic forms. In the current study we characterized the activity of human placental NAT and deacetylase toward the carcinogenic arylamine, 2-aminofluorene (AF) and its acetylated metabolite, 2-acetylaminofluorene (AAF). 2-Aminofluorene is a synthetic, prototype carcinogenic arylamine compound, and its metabolism has been extensively studied in the laboratory. Our data show that the affinity (Km = 24.2 +/- 1.66 mumol/L; mean +/- SEM, n = 6) and maximal velocity (Vmax = 4.29 +/- 0.33 nmol/min/mg; mean +/- SEM, n = 6) of AF N-acetylation by human placenta are similar to those in human liver. The deacetylation of AAF to AF by placental microsomes may be catalyzed by a carboxylesterase. However, our studies with inhibitors reveal that the characteristics of human placental deacetylation activity differ from that of human liver.(ABSTRACT TRUNCATED AT 250 WORDS)
Division of Pharmacology and Toxicology, Hospital for Sick Children, Toronto, Ontario, Canada.
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Derewlany
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Koren
D015073:2-Acetylaminofluorene / Q000493:pharmacokinetics*; D000107:Acetylation / Q000187:drug effects; D001711:Biotransformation; D002273:Carcinogens / Q000493:pharmacokinetics*; D005260:Female; D005449:Fluorenes / Q000493:pharmacokinetics*; D006801:Humans; D017953:Isocyanates / Q000494:pharmacology; D008862:Microsomes, Liver / Q000378:metabolism; D009596:Nitrophenols / Q000494:pharmacology; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy
D002273:Carcinogens; D005449:Fluorenes; D017953:Isocyanates; D009596:Nitrophenols; C006995:2-chloroethyl isocyanate; C012177:2-aminofluorene; C002887:bis(4-nitrophenyl)phosphate; C008642:4-nitrophenyl acetate; D015073:2-Acetylaminofluorene