Study on Effects of p-Phenylbenzoic Acid on Change of Sulfation and Glucuronidation in Rats.

The effects of p-phenylbenzoic acid (PPBA) on sulfation and glucuronidation was studied in rats. Following intravenous injection of 14C-p-tert-butylphenol (14C-TB, 50 micromol/kg) with PPBA (50 micromol/kg), the sulfation of 14C-TB was decreased by 38.8% and its glucuronidation increased by 62.3%. In a system of isolated hepatocytes, the sulfation of 14C-TB increased and its glucuronidation decreased following the addition of 100 microM of PPBA, suggesting competitive inhibition by the glucuronidation of PPBA. On the other hand, the sulfation of 14C-TB decreased and its glucuronidation increased following the addition of 400 microM of PPBA, which represents the plasma concentration of PPBA in vivo. At this concentration, significant leakage of GOT, GPT and LDH into the medium was observed, whereas, no significant change in the ATP synthesis was noted. Microsomes preincubated with 60 microM of PPBA, which represents the intracellular concentration of PPBA in the liver in vivo, showed no change in the level of glucuronidation of 14C-TB. These results suggest that PPBA in the plasma injures cell membranes and causes a leakage of cytosolic sulfotransferase, whereas UDPGT, embedded in the microsomal membrane, does not leak from the injured cell membrane, resulting in the decrease in sulfation and increase in glucuronidation. Similar in vivo effects on the sulfation/glucuronidation ratio were observed for benzoic acids substituted with benzoyl and phenoxy groups.