Volume 7 Supplement 2
Impact of stereochemistry on biological effects of permethrin: induction of apoptosis in human hepatoma cells (HCC-1.2) and primary rat hepatocyte cultures
© Dornetshuber et al; licensee BioMed Central Ltd. 2007
Published: 14 November 2007
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 [1–3]. 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.
- Gassner B, Wüthrich A, Scholtysik G, Solioz M: The pyrethroids permethrin and cyhalothrin are potent inhibitors of the mitochondrial complex I. J Pharmacol Exp Ther. 1997, 281: 855-860.PubMedGoogle Scholar
- Kostka G, Palut D, Kopeć-Szlezak J, Ludwicki JK: Early hepatic changes in rats induced by permethrin in comparison with DDT. Toxicology. 2000, 142: 135-143. 10.1016/S0300-483X(99)00164-X.View ArticlePubMedGoogle Scholar
- Heder AF, Hirsch-Ernst KI, Bauer D, Kahl GF, Desel H: Induction of cytochrome P450 2B1 by pyrethroids in primary rat hepatocyte cultures. Biochem Pharmacol. 2001, 62: 71-79. 10.1016/S0006-2952(01)00639-6.View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd.