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Chelator in Environmentally-exposed Poor Detoxifiers: An Adjuvant Hepatoprotective Treatment for Poly-drug Users?

Abstract

Makida Y, He F, Mohania D, Balieiro-Neto G, Alagozlu H, Pathak S, Naito Y, Lorenzetti A, Takadanohara H, Cervi J and Marotta F

Glutathione-S-Transferase (GST) genes, including GSTT1, GSTP1, and GSTM1, play a major role in detoxification and metabolism of xenobiotics. The aim of the present study was to test an orally bioavailable GSH-based compound in poor detoxifier subjects regarding their oxidative stress, ammonia metabolism and heavy metal clearance. Eligibility was established with a telephone questionnaire followed by a clinical examination to obtain height, weight, blood pressure and screening blood chemistry and GSTM-1 gene test. Seventy-five GSTM1-null, non-smoking healthy individuals were introduced in the study who were teetotallers or were using a maximum of 20 g alcohol/day men (n = 47) and women (n = 28) aged 38-69 years (mean: 49.7) with body-mass index ranging from 22 to 29 kg/m2) participated in the study. All enrolled participants were free from acute or chronic diseases and did not eat a diet or take medications that might interfere with outcome markers namely antioxidant supplements, high intake of dietary polyphenols including coffee, grapefruit juice or anti-inflammatory medications. Subjects were divided in 3 groups (25 subjects each): a) Given an oral bioabsorbable glutathione-based compound added with selenium, L-cysteine and vitamin C (GLU-9599, Named Research Co., Lesmo, Italy) at the dosage of 1 tab a day for two months; b) 600 mg of glutathione in 250 saline, given intravenously over 90 min, twice a week for 2 months; and c) Given 3 g a day of a strong cation-exchange oral chelator consisting of a mixture of chabasite-phillipsite for two months. Dietary questionnaire was administered to all subjects. Either at baseline, at one month or at the end of the study the following parameters were tested: erythrocytes (RBC) level of GSH/GSSG and Glutathione Peroxidise (GPx), urinary 8-OHdG, 24 h urinary measurement of main heavy metals, faecal metals, ammonia and oxidative stress. GLU-9599 showed to significantly lower either RBC oxidative stress or urinary 8-OHdG as compared to either IV glutathione or oral chelator (p<0.01). There was a significant correlation between urinary 8-OHdG and overall heavy metal excretion (r: 0.58, p<0.005) but no correlation occurred with RBC oxidative stress. Few subjects with fatty liver and abnormal transaminases improved their value during treatment with GLU-9599. Only oral chelator was effective in significantly lower faecal metals, ammonia and faecal oxidative stress (p<0.005). There was a not significant trend increase of mercury faecal excretion and GLU-9599. Overall, it would appear that in poor-detoxifier (GSTM1-null genotype) subjects, an effective orally-absorbable stabilised-glutathione can efficiently restore antioxidant defences in view of a potential wider application as an integrative adjuvant co-treatment in patients environmentally-exposed and also under pharmacological burden. Effective heavy metal clearance remains a still unresolved issue which may benefit from the rational addition of high cation-exchange oral chelators with a likely association with viable glutathione supplements too.