Xenobiotics biotransformation / detoxification and human variability in toxicokinetic

The xenobiotics we are daily exposed via the environment, water and food once absorbed can be bioactivated to more toxic compounds and/or detoxificated by specific enzymes such as the Glutathione-S-Transferases (GSTs) or the cytochromes P450 (CYPs), characterized by polymorphic isoforms, giving rise to interindividual metabolic differences. The identification of the human GSTs or CYPs isoform involved might evidence groups of population more susceptible to xenobiotic toxic effects. This work is part of an European project financed by EFSA aimed to modeling the kinetics variability to predict the dynamic variability The first part of the study has been focused on the metabolic pathway Microcystins (MCs), a group of >200 natural toxins present in freshwater, possible contaminants of drinking water and fish. They are characterized by different in vivo toxicity, which has been related to different kintetics; their detoxification is mediated by glutathione (GSH) conjugation, catalyzed by the GSTs. The kinetics parameters for the variants MC-LW, YR (Vmax, Km and Cli) of MC-LW and YR were calculated and results indicated that the efficiencies of the single human recombinant GSTs are quite similar (0.027-0.066 pmolGSMC-LW/(μgprot*min*μM) and 0.044-0.076 pmolGSMC-YR/(μgprot*min*μM); the highest Cli were shown by GSTP1 and A1 for MC-LW and P1=O1>A1 for MC-YR. Comparing these results with previous data on MC-LR and MC-RR (1,2), the least toxic (MC-RR) appears to be the one which is most efficiently detoxified. The next step will be the study of the bioactivation of the organophosphorotionate insecticide Phosmet mediated by CYPs, (work in progress). . 1)Buratti F.M. et al 2011 Chem. Res. Toxicol. 24, 926-933 2)Buratti F.M. et al 2013 Toxicol. Letters 219, 231– 238 .