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Glutathione depletion in rat hepatocytes : a mixture toxicity study with alpha,ß-unsaturated esters

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Author: Freidig, A. · Hofhuis, M. · Holstijn, I. van · Hermens, J.
Institution: TNO Voeding
Source:Xenobiotica, 5, 31, 295-307
Identifier: 57058
doi: doi:10.1080/00498250110052733
Keywords: Nutrition · acrolein · acrylic acid · allyl compound · ester · glutathione · methacrylic acid · animal cell · article · chemical reaction · controlled study · cytotoxicity · in vitro study · liver toxicity · male · mathematical analysis · nonhuman · protein content · rat · reaction analysis · risk assessment · Acetaldehyde · Acrolein · Animals · Cell Survival · Cells, Cultured · Dose-Response Relationship, Drug · Esters · Fumarates · Glutathione · Hepatocytes · Male · Methacrylates · Models, Statistical · Rats · Rats, Wistar · Animalia


Glutathione (GSH) depletion is often reported as an early cytotoxic effect, caused by many reactive organic chemicals. In the present study, GSH depletion in primary rat hepatocytes was used as an in vitro effect-equivalent to measure the toxic potency of α,β-unsaturated esters (acrylates and methacrylates). 2. When these compounds were administered as a mixture, GSH depletion was dose additive. The result of the mixture study shows that GSH depletion may be a useful effect-equivalent for the risk assessment of mixtures of α,β-unsaturated esters. 3. To get more insight in the underlying mechanisms of GSH depletion, the metabolism of two esters was investigated in greater detail. One of them, allyl methacrylate, was metabolized to acrolein. This metabolic pathway can explain the high potency of allyl methacrylate to deplete GSH despite its low intrinsic chemical reactivity.