Impact of stereochemistry on biological effects of permethrin: induction of apoptosis in human hepatoma cells (HCC-1.2) and primary rat hepatocyte cultures
KeywordsTest Model Insecticidal Action Human Hepatoma Cell Cytochrome P450 Enzyme Mitochondrial Complex
Stereochemistry plays a crucial role in determining the toxicological profile of many chiral xenobiotics, e.g. the insecticidal action of mixtures containing the four stereoisomers of permethrin is essentially brought about by the (1R, cis)- and (1R, trans)-forms. Primarily non-ion channel related mammalian effects like induction of cytochrome P450 enzymes and inhibition of mitochondrial complex I – relevant endpoints in elucidating a chemical's mode of action and thus toxicological risk assessment – were elucidated in studies with four-isomer mixtures of permethrin only [1, 2, 3]. Therefore, we initiated a project to shed light on the stereoselectivity of permethrin effects in mammals, using human hepatoma cells (HCC-1.2) and primary rat hepatocyte cultures as test models. Here we report (1) a commercially available four-isomer mixture of permethrin (cis-racemate/trans-racemate ~ 25:75) exhibited a dose-dependent (2–50 μM) pro-apoptotic activity; (2) the physiological death signal TGF-β1 (10 ng/ml) and permethrin exerted an additive pro-apoptotic effect; (3) purified permethrin stereoisomers, i.e. (1R, cis), (1S, cis), (1R, trans), (1S, trans), exhibited – in contrast to their insecticidal action – no significant differences in their pro-apoptotic action as compared to the four-isomer mixture; (4) the pro-apoptotic potency of permethrin was lost upon metabolism to permethrinic acid, 3-phenoxybenzyl alcohol, and 3-phenoxybenzoic acid.
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