HUMAN PLACENTAL-TRANSFER AND METABOLISM OF P-AMINOBENZOIC ACID

Studies in our laboratory have shown that the N-acetylation activity o f the human term placenta is predominantly attributable to the NAT1 fo rm of arylamine N-acetyltransferase (NAT). To further assess the acety lation capacity of the placenta, the N-acetylation of the prototype NA T1-selective substrate, p-aminobenzoic 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 ace tylation activity observed in a subcellular fraction (cytosol). Such s tudies 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 ven ous samples taken less than 5 min from the start of perfusion with PAB A. In a closed recirculating system, the rate of placental PABA transf er decreased as PABA concentrations equilibrated across the placenta. In contrast, the rate of N-acetyl-p-aminobenzoic acid formation contin ued to increase throughout the entire time of perfusion. Kinetic param eters of PABA N-acetylation measured in cytosol prepared from perfused placental tissue show that the placenta retains its ability to N-acet ylate PABA at fresh tissue levels even after 6 hr of in vitro perfusio n (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 indica te that the human placenta has a significant capacity to N-acetylate N AT1-selective substrates of NAT and that it maintains its ability to m etabolize xenobiotics during in vitro perfusion. The placental N-acety lation of therapeutic substrates such as the sulfonamide antibiotics m ay influence the disposition of these agents in pregnancy. N-acetylati on may also play an important toxicologic role in the metabolism of an other class of NAT substrate, the carcinogenic arylamines.