title: LLU-alpha, an endogenous metabolite of gamma-tocopherol, is more effective against metal nephrotoxicity in rats than gamma-tocopherol.
abstract: Antioxidants of the vitamin E family have protective effects against metal toxicity. We examined the protective effect of racemic LLU-alpha [2,7,8-trimethyl-2-(carboxyethyl)-6-hydroxychroman] a metabolite of gamma-tocopherol, in comparison to the effect of alpha- and gamma-tocopherol in rats treated with sodium dichromate (Cr) or thallium sulfate (Tl). We measured metal nephrotoxicity based on urinary protein excretion and discussed it with respect to the metal concentration in renal tissue. The ranking of antioxidant activity (iron stimulated lipid peroxidation, luminol and lucigenin amplified chemiluminescence) was determined in the following order: alpha-tocopherol<gamma-tocopherol<LLU-alpha. Pretreatment with LLU-alpha produced lower chromate nephrotoxicity than alpha- or gamma-tocopherol, but did not influence Cr concentration in renal tissue. The protective effect of LLU-alpha against Cr toxicity seemed to be caused by its stronger antioxidant activity in comparison to alpha- and gamma-tocopherol. Pretreatment with LLU-alpha resulted in lower thallium-induced proteinuria, a lower concentration of Tl in the renal medulla, and higher urinary Tl excretion. Unlike LLU-alpha, which has been shown to inhibit K(+) channels in the apical membrane of the thick ascending limb of Henle's loop, we found that gamma-tocopherol did not. This finding reaffirmed the similarity between K(+) and Tl(+) and also explained the significantly decreased Tl concentration in the renal medulla in rats treated with LLU-alpha. We speculate that the protective effect of LLU-alpha against Tl nephrotoxicity is caused both by its antioxidant effect and, at least in part, by its ability to decrease Tl concentration as a consequence of inhibited Tl(+) uptake through K(+) channels. This finding confirmed the similarity between K(+) and Tl(+) and also explained the significantly decreased Tl concentration in the renal medulla in rats treated with LLU-alpha.
authors.affiliation: Institute of Pharmacology and Toxicology, Friedrich Schiller University, D-07740 Jena, Germany. dapp@mti-n.uni-jena.de
authors.forename: D
authors.initials: D
authors.lastname: Appenroth
authors.forename: E
authors.initials: E
authors.lastname: Karge
authors.forename: G
authors.initials: G
authors.lastname: Kiessling
authors.forename: W J
authors.initials: WJ
authors.lastname: Wechter
authors.forename: K
authors.initials: K
authors.lastname: Winnefeld
authors.forename: C
authors.initials: C
authors.lastname: Fleck
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology*; D002839:Chromans / Q000097:blood / Q000494:pharmacology*; D002840:Chromates / Q000097:blood / Q000633:toxicity; D005260:Female; D007668:Kidney / Q000187:drug effects*; D008163:Luminescent Measurements; D008670:Metals / Q000097:blood / Q000633:toxicity*; D015221:Potassium Channels / Q000187:drug effects; D011422:Propionates / Q000097:blood / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013793:Thallium / Q000097:blood / Q000633:toxicity; D014810:Vitamin E / Q000097:blood / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D002839:Chromans; D002840:Chromates; D008670:Metals; D015221:Potassium Channels; D011422:Propionates; D014810:Vitamin E; C107690:2,7,8-trimethyl-2-(beta-carboxyethyl)-6-hydroxychroman; D013793:Thallium; C016104:sodium bichromate; C013707:thallium sulfate