Biotransformation of carcinogenic arylamines and arylamides by human placenta

Lidia O. Derewlany, Gideon Koren

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

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 μmol/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. Because reactive arylamine and arylamide metabolites are teratogenic to embryos of laboratory animals, the balance between placental acetylation and deacetylation reactions may be of toxicologic importance to the developing human fetus, which is susceptible to toxic insults, especially during the early stages of gestation when the fetal ability to detoxify is low or absent.

Original languageEnglish
Pages (from-to)134-141
Number of pages8
JournalTranslational Research
Volume124
Issue number1
StatePublished - Jul 1994
Externally publishedYes

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