CYTOTOXICITY OF A SERIES OF MONO-SUBSTITUTED AND DISUBSTITUTED THIOUREA IN FRESHLY ISOLATED RAT HEPATOCYTES - A PRELIMINARY STRUCTURE-TOXICITY RELATIONSHIP STUDY

The cytotoxicity of a series of 12 mono- and 4 di-substituted thiourea containing compounds in freshly isolated rat hepatocytes was investig ated. It was found that thiourea toxicity, as evidenced by an increase in LDH-leakage from the cells, was accompanied by a depletion of intr acellular glutathione (GSH). No increase in lipid peroxidation was obs erved with any of the thiourea. Burimamide and thioperamide, thiourea- containing histamine receptor ligands, were also found to deplete intr acellular GSH. A clear structure-toxicity relationship was uncovered a mong a homologous series of N-phenylalkylthiourea. N-benzylthiourea (B TU) and N-phenylethylthiourea (PETU) were found to be non-toxic at a c oncentration of 1 mM, while N-phenylpropylthiourea (PPTU) and N-phenyl butylthiourea (PBTU) were found to cause significant LDH-leakage from the cells, accompanied by a depletion of intracellular GSH. This struc ture-toxicity relationship was further investigated using hepatocytes of differentially induced rats, however, no significantly different re sults were obtained when using hepatocytes of rats induced with phenob arbital (PB) or beta-naphthoflavone (BNF). Oxidation of the thiourea m oiety is thought to be the first step in the bioactivation of thiourea containing compounds. The oxidation of thiocholine sulfenic acids, pr oduced by FMO-mediated oxidation of the thiourea moiety, was used to d etermine whether the compounds examined are substrates for the FMO enz ymes in rat liver. No clear relationship was found between cytotoxicit y of the mono-substituted thiourea and lipophilicity of the N-substitu ent, nor with the FMO-mediated oxidation of the thionosulfur atom of t he mono-substituted thiourea. It is concluded from this study, that th iourea toxicity in rat hepatocytes is structure-dependent and manifest s itself as LDH-leakage and as a depletion of intracellular non-protei n sulfhydryls, notably GSH, most likely followed by alkylation of vita l macromolecular structures. Published by Elsevier Science Ireland Ltd . All rights reserved.