228 ISSN 1990-7508, Biochemistry (Moscow), Supplement Series B: Biomedical Chemistry, 2019, Vol. 13, No. 3, pp. 228–236. © Pleiades Publishing, Ltd., 2019. Russian Text © The Author(s), 2019, published in Biomeditsinskaya Khimiya. Computer-Aided Xenobiotic Toxicity Prediction Taking into Account Their Metabolism in the Human Body A. V. Rudik a, *, A. V. Dmitriev a , A. A. Lagunin a, b , S. M. Ivanov a, b , D. A. Filimonov a , and V. V. Poroikov a a Institute of Biomedical Chemistry, ul. Pogodinskaya 10, Moscow, 119121 Russia b Medico-Biological Faculty, Pirogov Russian National Research Medical University (RNRMU), ul. Ostrovityanova 1, Moscow, 117997 Russia *e-mail: rudik_anastassia@mail.ru Received January 18, 2019; revised March 18, 2019; accepted March 18, 2019 Abstract—Most xenobiotics undergo metabolic conversions in the human body. The biological activity, tox- icity, and other properties of such metabolites may significantly differ from those of the parent compounds. Not only xenobiotics and their final metabolites produced in large quantities, but the intermediates and final metabolites formed in trace amounts, can cause undesirable effects. We have developed a freely available web application MetaTox (http://www.way2drug.com/mg/) for integral assessment of xenobiotics toxicity taking into account their metabolism in humans. The generation of the metabolite structures is based on the reaction fragments. The probability estimation of the certain reaction and the probability estimation of the atoms, which are changed during biotransformation, are used for generation of the xenobiotic metabolism pathways. The MetaTox web application assesses metabolism of compounds in humans and evaluates their acute toxic- ity, specific (cardiotoxicity, hepatotoxicity, nephrotoxicity), and chronic toxicity (carcinogenicity, teratoge- nicity, mutagenicity, effects on the reproductive system). Keywords: biotransformation, metabolism, prediction, toxicity, PASS, MetaTox web application DOI: 10.1134/S1990750819030065 INTRODUCTION Most xenobiotics, which include pharmaceutical substances, food additives, cosmetics, substances of plant origin, industrial ecotoxicants, etc., undergo biotransformation, involving various enzymes; this is one of the most important mechanisms of the detoxi- fication protective process, which mainly occurs in the liver. Biotransformation of xenobiotics can include several stages, thus forming a metabolic pathway for a particular compound. In a normally functioning liver, two types of biotransformation reactions take place; these are usually classified as phase I and phase II reactions [1]. During phase I reactions hydrophobic molecules are transformed into more polar, hydro- philic metabolites, which are more easily excreted by the excretory system via oxidation, reduction or hydrolysis [2]. Typical and most common enzymes involved in phase I metabolism are enzymes from the family of cytochromes P450, catalyzing oxidation of xenobiotics. Phase II reactions of biotransformation (also known as conjugation phase) involve various transferases; the most common form of conjugation of exogenous compounds is the reaction of glucuronide formation catalyzed by UDP-glucuronyl transferases. Conjugates are also more polar and more soluble in water than parent substances and therefore they are more readily excreted from the body. Although in most cases the biotransformation pro- cess results in formation of less active metabolites, there is evidence for formation of xenobiotic metabo- lites exhibiting higher toxicity [3] or reactivity [4]. Since not only xenobiotics and their final metabolites, formed in large quantities, but also intermediate and final metabolites, formed in trace amounts, may exhibit toxic effects, evaluation of xenobiotic toxicity, taking into account their metabolism in the human body, is an important task for basic research in medi- cine and toxicology. Preclinical studies aimed at determination of metabolites formed during biotransformation of drug candidate compounds for analysis of their potential toxic effects, include both animal experiments in vivo and in vitro studies employing various cells and tissues and animal organs [5]. However, such biotransformation studies are asso- ciated with certain difficulties, since the metabolic transformations of xenobiotics in experimental ani- mals may be completely different from their biotrans- formation in the human body [6]. Therefore, there is a clear need in development of computerized prediction methods applicable for evaluation of pharmacokinet-