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 a 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-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 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 (Vmax = 5.75 +/- 0.42 nmol/min/mg (fresh) vs. Vmax = 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Derewlany
L O
LO
Division of Pharmacology and Toxicology, Hospital for Sick Children, Toronto, Ontario, Canada.
Knie
B
B
Koren
G
G
D010129:4-Aminobenzoic Acid / Q000378:metabolism*; D000107:Acetylation; D001191:Arylamine N-Acetyltransferase / Q000378:metabolism*; D003600:Cytosol / Q000201:enzymology / Q000378:metabolism; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008431:Maternal-Fetal Exchange; D010477:Perfusion; D010920:Placenta / Q000201:enzymology*; D011247:Pregnancy
D001191:Arylamine N-Acetyltransferase; D010129:4-Aminobenzoic Acid