Organochlorines inhibit acetaminophen glucuronidation by redirecting UDP-glucuronic acid towards the D-glucuronate pathway

Toxicology and Applied Pharmacology
Tom S ChanPeter J O'Brien

Abstract

Industry-derived organochlorines are persistent environmental pollutants that are a continuing health concern. The effects of these compounds on drug metabolism are not well understood. In the current study we present evidence that the inhibition of acetaminophen (APAP) glucuronidation by minute concentrations of organochlorines correlates well with their ability to stimulate the d-glucuronate pathway leading to ascorbate synthesis. A set of 6 arylated organochlorines, including 5 PCB (polychlorinated biphenyl) congeners, were assessed for their effects on APAP glucuronidation in isolated hepatocytes from male Sprague-Dawley rats. The capacity of each organochlorine to inhibit APAP glucuronidation was found to be directly proportional to its capacity to stimulate ascorbate synthesis. PCB153, PCB28 and bis-(4-chlorophenyl sulfone) (BCPS) in increasing order were the most effective organochlorines for inhibiting APAP glucuronidation and stimulating the d-glucuronate pathway. None of the 3 inhibitors of APAP glucuronidation were able to alter the expression of UGT1A6, UGT1A7 and UGT1A8 (the major isoforms responsible for APAP glucuronidation in the rat), however, their efficacy at inhibiting APAP glucuronidation was proportional t...Continue Reading

Citations

Nov 19, 2010·Analytical Chemistry·Karthikeshwar VangalaDongmao Zhang
Mar 31, 2009·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·R PoonG Pelletier
Mar 31, 2016·International Journal of Environmental Research and Public Health·Maria Nicolà D'ErricoLeonardo Soleo
Sep 27, 2012·European Journal of Pharmacology·Letizia AntonilliPaolo Nencini
Feb 18, 2010·Dalton Transactions : an International Journal of Inorganic Chemistry·Juan Carlos GonzálezSandra Signorella

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