DIFFERENT MECHANISM OF SATURATION OF ACETAMINOPHEN SULFATE CONJUGATION IN MICE AND RATS

Sulfation of acetaminophen is a high-affinity and low-capacity conjuga tion pathway in rats. It is thought that sulfation becomes saturated i n rats at high doses of acetaminophen because of limited availability of the active sulfate donor, 3'-phosphoadenosine 5'-phosphosulfate (PA PS), the supply of which is, in turn, limited by the availability of i ts precursor, inorganic sulfate. The present study was designed to det ermine whether a similar mechanism is responsible for capacity-limited sulfation in mice. Saturation of acetaminophen sulfation occurs in bo th species; however, at the maximal rate of sulfation, sulfate and PAP S concentrations were markedly decreased in rats but not in mice. Admi nistration of sodium sulfate and the sulfate precursor N-acetylcystein e enhanced the formation of acetaminophen sulfate in rats, but not in mice. Mice exhibited lower activities of hepatic PAPS synthetic enzyme s (i.e., ATP sulfurylase and APS kinase) and sulfotransferase than rat s, which may in part be responsible for their lower capacity to sulfat e acetaminophen. In addition, administration of acetaminophen further decreased phenolsulfotransferase activity in mice. In rats, administra tion of acetaminophen did not influence hepatic sulfotransferase activ ity. These observations suggest that while the capacity of rats to sul fate acetaminophen is limited by the availability of PAPS, in mice it is limited by sulfotransferase activity. (C) 1996 Academic Press, Inc.