Effects of molybdate and pentachlorophenol on the sulfation of dehydroepiandrosterone.
Pentachlorophenol (PCP) and molybdate have been shown to inhibit the sulfoconjugation of various chemicals in rats and therefore are useful to examine the role of sulfoconjugation on the toxicity of a chemical. PCP inhibits sulfation by competing with substrates for phenol-sulfotransferases, but not hydroxysteroid-sulfotransferases. In contrast, molybdate decreases sulfation by limiting sulfate availability and thereby decreasing the synthesis of 3'-phosphoadenosine 5'-phosphosulfate (PAPS), which is the obligate cosubstrate for sulfation. Therefore, it was of interest to determine whether PCP or molybdate is effective in decreasing the in vivo sulfation of dehydroepiandrosterone (DHEA), which is a substrate for hydroxysteroid-sulfotransferases. PCP (40 micromol/kg ip) or molybdate (7.5 mmol/kg po) was given 45 min and 4 h, respectively, prior to the start of DHEA infusion. The effects of these two sulfation inhibitors on DHEA sulfation were dependent on the rate of DHEA infusion in rats. PCP had different effects on the sulfation of various infusion rates of DHEA in rats. PCP had little effect on the sulfation after the two lowest infusion rates of DHEA (12.5 and 25 mg/kg) and actually increased (233%) DHEA-sulfate serum concentrations with the highest DHEA infusion rate (50 mg/kg). Although molybdate had little affect on the sulfation of the lowest DHEA infusion rate, it significantly decreased (50-85%) DHEA-sulfate serum concentrations with the two higher DHEA infusion rates. These data indicate that molybdate, unlike PCP, decreases the sulfation of DHEA and may be a useful tool to decrease the sulfation of other substrates of hydroxysteroid-sulfotransferases.
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, 66160-7417, USA.
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Boles
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Klaassen
D000818:Animals; D015239:Arylsulfotransferase / Q000037:antagonists & inhibitors*; D003687:Dehydroepiandrosterone / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D007262:Infusions, Intravenous; D008982:Molybdenum / Q000737:chemistry / Q000494:pharmacology*; D010416:Pentachlorophenol / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013379:Substrate Specificity; D013431:Sulfates / Q000097:blood; D015238:Sulfotransferases / Q000037:antagonists & inhibitors
D004791:Enzyme Inhibitors; D013431:Sulfates; C044659:molybdate; D003687:Dehydroepiandrosterone; D008982:Molybdenum; D010416:Pentachlorophenol; C022321:PAPS sulfotransferase; D015238:Sulfotransferases; D015239:Arylsulfotransferase