Effects of molybdate and pentachlorophenol on the sulfation of acetaminophen.
Pentachlorophenol (PCP) is an inhibitor of phenol-sulfotransferases and has been used to ascertain the role of sulfation in toxicology. Recently, molybdate has been shown to inhibit the sulfation of various chemicals by decreasing hepatic concentrations of the cosubstrate, 3'-phosphoadenosine 5'-phosphosulfate (PAPS). The purpose of this study was to compare the effectiveness of these two chemicals in inhibiting the sulfation of various doses of acetaminophen (AA) in the rat. PCP (40 micromol/kg) decreased the 2-h combined biliary and urinary excretion of AA-sulfate by 78, 83, 84, and 47% of the 0.1, 0.3, 1, and 3 mmol/kg doses of AA, respectively. Molybdate (7.5 mmol/kg) decreased the sulfation of these same doses of AA by 50, 65, 62, and 81%, respectively. These data indicate that PCP is more effective in decreasing the sulfation of low than high doses of AA, which may result from less AA, at lower doses, to compete with PCP for sulfotransferases. Conversely, molybdate is more effective in decreasing sulfation of high rather than low doses of AA because molybdate decreases sulfate availability and decreases PAPS synthesis. More PAPS is required for the sulfation of high than low doses of AA. Therefore, PCP inhibits sulfation more effectively at low doses of AA when sulfation is limited by sulfotransferases, and molybdate inhibits sulfation more effectively at high doses of AA when sulfation is limited by PAPS.
Boles
J W
JW
Center for Environmental and Occupational Health, Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160-7417, USA.
Klaassen
C D
CD
D000082:Acetaminophen / Q000097:blood / Q000378:metabolism* / Q000652:urine; D018712:Analgesics, Non-Narcotic / Q000097:blood / Q000378:metabolism* / Q000652:urine; D000818:Animals; D001646:Bile / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000633:toxicity*; D008297:Male; D008982:Molybdenum / Q000633:toxicity*; D010416:Pentachlorophenol / Q000633:toxicity*; D010724:Phosphoadenosine Phosphosulfate / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013056:Spectrophotometry, Ultraviolet
D018712:Analgesics, Non-Narcotic; D004791:Enzyme Inhibitors; C044659:molybdate; D000082:Acetaminophen; D010724:Phosphoadenosine Phosphosulfate; D008982:Molybdenum; D010416:Pentachlorophenol