In vitro inhibition of mouse and rat glutathione S-transferases by di(2-ethylhexyl) phthalate, mono(2-ethylhexyl) phthalate, 2-ethylhexanol, 2-ethylhexanoic acid and clofibric acid.
The in vitro inhibitory response of mouse and rat liver cytosolic glutathione S-transferase (GST) activities using the substrates 1,2-dichloro-4-nitrobenzene (DCNB) and 1,2-epoxy-3-(p-nitrophenoxy)propane (ENPP) was determined for the peroxisome proliferators di(2-ethylhexyl) phthalate (DEHP), mono(2-ethylhexyl) phthalate (MEHP), 2-ethylhexanol, 2-ethylhexanoic acid and clofibric acid. MEHP was a potent inhibitor of GST activities in both species, with IC(50)s for DCNB and ENPP of 0.34 and 0.10 mm in the mouse, and 0.32 and 0.88 mm in the rat, respectively. DEHP demonstrated substrate specificity; it inhibited the DCNB-transferase with IC(50)s of 1.05 and 0.55 mm in the mouse and rat, respectively. The other compounds were moderate to weak inhibitors. The inhibitory potency ranking of these compounds was qualitatively similar in both species. Quantitatively, the DCNB-transferase was more sensitive in rats, while ENPP-transferase was more sensitive in mice. The in vitro inhibition may explain, in part, decreases in GST activity seen in vivo following treatment with these compounds. The finding of low IC(50)s for the inhibition of GST activity(s) by MEHP and DEHP in the rat and mouse livers strongly suggests that further studies should be conducted to test for the potential of these compounds to inhibit human liver GST.
Law
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Center for Human Toxicology, Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, Utah 84112, USA.
Moody
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DE