title: Anethole dithiolethione lowers the homocysteine and raises the glutathione levels in solid tissues and plasma of rats: a novel non-vitamin homocysteine-lowering agent.
abstract: High homocysteine (Hcys) levels are suspected to contribute to the pathogenesis of cardiovascular disease and of other chronic conditions. Failure of B vitamins to reduce the incidence of cardiovascular events while lowering the Hcys levels, has prompted the search for alternative treatments. We tested the ability of anethole dithiolethione (ADT) to lower the Hcys levels in rats and we explored possible underlying mechanisms. Parenteral administration of 10mg/kg ADT to normal rats for 3 days lowered the Hcys levels between 51.4% and 31.5% in kidneys, liver, testis and plasma. Concomitantly, glutathione (GSH) increased between 112% and 28% in kidneys, brain, liver and plasma whereas protein thiolation index decreased 30%. In hyperhomocysteinemic rats, the plasma Hcys levels dropped 70% following a single ip injection of 10mg/kg ADT, while they decreased 55% following oral administration of 2mg/kg/day ADT for one week. Significant additive effects occurred when sub-therapeutic doses of ADT and folic acid were used in combination. To test the possible mechanism(s) of these actions, we perfused isolated rat livers and kidneys with albumin-bound Hcys, the prevalent form of plasma Hcys, and physiological thiols and disulfides at different ratios. In both organ preparations, the elimination rate of albumin-bound Hcys was progressively faster as the amount of reduced thiols was increased in the perfusate. These findings indicate that ADT shifts the redox ratio of GSH and other thiols with their oxidized forms toward the reduced forms, thus favoring the dissociation of albumin-bound Hcys and its transfer to renal and hepatic cells for further processing.
authors.affiliation: Department of Life Sciences, Laboratory of Pharmacology and Toxicology, University of Siena, Via A. Moro 4, I-53100 Siena, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Giustarini
authors.affiliation: Division of Nephrology, Department of Medicine, The University of Texas Health Science Center San Antonio, San Antonio, TX 78229, USA; Audie L. Murphy VA Hospital, San Antonio, TX 78229, USA.
authors.forename: Paolo
authors.initials: P
authors.lastname: Fanti
authors.affiliation: Department of Pharmaceutical Sciences, University of Milan, Via L. Mangiagalli, 25, 20133 Milano, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Sparatore
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 67, 56126 Pisa, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Matteucci
authors.affiliation: Department of Life Sciences, Laboratory of Pharmacology and Toxicology, University of Siena, Via A. Moro 4, I-53100 Siena, Italy. Electronic address: ranieri@unisi.it.
authors.forename: Ranieri
authors.initials: R
authors.lastname: Rossi
mesh_terms: D000781:Anethole Trithione / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D005978:Glutathione / Q000096:biosynthesis / Q000097:blood / Q000378:metabolism*; D006710:Homocysteine / Q000037:antagonists & inhibitors* / Q000097:blood / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D006710:Homocysteine; D005978:Glutathione; D000781:Anethole Trithione
keywords: Anethole dithiolethione; Hyperhomocysteinemia; Protein-bound homocysteine; Thiols