Human placental transfer and metabolism of p-aminobenzoic acid

Studies in our laboratory have shown that the N-acetylation activity of the human term placenta is predominantly attributable to the NAT1 form of arylamine N-acetyltransferase (NAT). To further assess the acetylation capacity of the placenta, the N-acetylation of the prototype NAT1-selective substrate, p-amino-benzoic acid (PABA), was studied using the in vitro human placental perfusion model. This study compared the net N-acetylation of PABA in intact placental tissue with the PABA acetylation activity observed in a subcellular fraction (cytosol). Such studies with intact tissue can permit assessment of the exposure of the fetus in vivo to drugs and their metabolites. Acetylated metabolite (N-acetyl-p-aminobenzoic acid) was detectable in fetal and maternal venous samples taken less than 5 min from the start of perfusion with PABA. In a closed recirculating system, the rate of placental PABA transfer decreased as PABA concentrations equilibrated across the placenta. In contrast, the rate of N-acetyl-p-aminobenzoic acid formation continued to increase throughout the entire time of perfusion. Kinetic parameters of PABA N-acetylation measured in cytosol prepared from perfused placental tissue show that the placenta retains its ability to N- acetylate PABA at fresh tissue levels even after 6 hr of in vitro perfusion (V(max) = 5.75 ± 0.42 nmol/min/mg (fresh) vs. V(max) = 7.24 ± 0.31 nmol/min/mg (perfused); mean ± S.E.M., n = 6). These studies indicate that the human placenta has a significant capacity to N-acetylate NAT1-selective substrates of NAT and that it maintains its ability to metabolize xenobiotics during in vitro perfusion. The placental N-acetylation of therapeutic substrates such as the sulfonamide antibiotics may influence the disposition of these agents in pregnancy. N-acetylation may also play an important toxicologic role in the metabolism of another class of NAT substrate, the carcinogenic arylamines.