Identification of structural alerts for liver and kidney toxicity using repeated dose toxicity data

BackgroundThe potential for a compound to cause hepatotoxicity and nephrotoxicity is a matter of extreme interest for human health risk assessment. To assess liver and kidney toxicity, repeated-dose toxicity (RDT) studies are conducted mainly on rodents. However, these tests are expensive, time-consuming and require large numbers of animals. For early toxicity screening, in silico models can be applied, reducing the costs, time and animals used. Among in silico approaches, structure–activity relationship (SAR) methods, based on the identification of chemical substructures (structural alerts, SAs) related to a particular activity (toxicity), are widely employed.ResultsWe identified and evaluated some SAs related to liver and kidney toxicity, using RDT data on rats taken from the hazard evaluation support system (HESS) database. We considered only SAs that gave the best percentages of true positives (TP).ConclusionsIt was not possible to assign an unambiguous mode of action for all the SAs, but a mechanistic explanation is provided for some of them. Such achievements may help in the early identification of liver and renal toxicity of substances.

[1]  Mathieu Vinken,et al.  The adverse outcome pathway concept: a pragmatic tool in toxicology. , 2013, Toxicology.

[2]  M. Perazella.  Crystal-induced acute renal failure. , 1999, The American journal of medicine.

[3]  K. Aldous,et al.  Mechanism of chloroform-induced renal toxicity: non-involvement of hepatic cytochrome P450-dependent metabolism. , 2008, Toxicology and applied pharmacology.

[4]  Y Sakuratani,et al.  Hazard Evaluation Support System (HESS) for predicting repeated dose toxicity using toxicological categories , 2013, SAR and QSAR in environmental research.

[5]  Dominic P. Williams,et al.  Idiosyncratic toxicity: the role of toxicophores and bioactivation. , 2003, Drug discovery today.

[6]  Ian A. Nicholls,et al.  Acute Toxicity-Supported Chronic Toxicity Prediction: A k-Nearest Neighbor Coupled Read-Across Strategy , 2015, International journal of molecular sciences.

[7]  J. Michałowicz,et al.  Phenols - sources and toxicity , 2007 .

[8]  Ernest Hodgson,et al.  IN VITRO METABOLISM OF NAPHTHALENE BY HUMAN LIVER MICROSOMAL CYTOCHROME P450 ENZYMES , 2006, Drug Metabolism and Disposition.

[9]  J. Sørensen,et al.  Microbial degradation of the benzonitrile herbicides dichlobenil, bromoxynil and ioxynil in soil and subsurface environments--insights into degradation pathways, persistent metabolites and involved degrader organisms. , 2008, Environmental pollution.

[10]  K R Przybylak,et al.  Hepatotoxicity: A scheme for generating chemical categories for read-across, structural alerts and insights into mechanism(s) of action , 2013, Critical reviews in toxicology.

[11]  Paolo Mazzatorta,et al.  Modeling Oral Rat Chronic Toxicity , 2008, J. Chem. Inf. Model..

[12]  J. G. Hengstler,et al.  Alternative methods to safety studies in experimental animals: role in the risk assessment of chemicals under the new European Chemicals Legislation (REACH) , 2008, Archives of Toxicology.

[13]  R. Novak,et al.  Cellular distribution of cytochromes P-450 in the rat kidney. , 1999, Drug metabolism and disposition: the biological fate of chemicals.

[14]  G. S. Rao,et al.  Biochemical changes induced by naphthalene after oral administration in albino rats. , 1981, Toxicology letters.

[15]  Ivanka Tsakovska,et al.  A Mini Review of Mammalian Toxicity (Q)SAR Models , 2008 .

[16]  R. García-Domenech,et al.  True prediction of lowest observed adverse effect levels , 2006, Molecular Diversity.

[17]  K. Yagi,et al.  Serum lipid peroxide levels of albino rats administered naphthalene. , 1986, Biochemistry international.

[18]  Yalei Zhang,et al.  Potential toxicity of sulfanilamide antibiotic: binding of sulfamethazine to human serum albumin. , 2012, The Science of the total environment.

[19]  D. Thompson,et al.  Quinone methide formation from para isomers of methylphenol (cresol), ethylphenol, and isopropylphenol: relationship to toxicity. , 1995, Chemical research in toxicology.

[20]  R. Schnellmann,et al.  Toxic nephropathy: environmental chemicals. , 2003, Seminars in nephrology.

[21]  D. Bagchi,et al.  Naphthalene-induced oxidative stress in rats and the protective effects of vitamin E succinate. , 1996, Free radical biology & medicine.

[22]  A. Ahmed,et al.  PROTECTIVE EFFECT OF GRAPE SEEDS PROANTHOCYANIDINS AGAINST NAPHTHALENE-INDUCED HEPATOTOXICITY IN RATS , 2007 .

[23]  Emilio Benfenati,et al.  A generalizable definition of chemical similarity for read-across , 2014, Journal of Cheminformatics.

[24]  Carol A Marchant,et al.  An Expert System Approach to the Assessment of Hepatotoxic Potential , 2009, Chemistry & biodiversity.

[25]  L. Pohl,et al.  Nephrotoxicity of chloroform: metabolism to phosgene by the mouse kidney. , 1984, Toxicology and applied pharmacology.

[26]  M. J. Coon,et al.  Cytochrome P-450 : multiplicity of isoforms, substrates, and catalytic and regulatory mechanisms , 1991 .

[27]  A. M. Ambrose,et al.  The reversible nephrotoxic effects of biphenyl , 1961 .

[28]  J. Angerer,et al.  Naphthalene—an environmental and occupational toxicant , 2003, International archives of occupational and environmental health.

[29]  LJ Lesko,et al.  Pharmacological Mechanism‐Based Drug Safety Assessment and Prediction , 2011, Clinical pharmacology and therapeutics.

[30]  Peter Willett,et al.  Similarity searching using 2D structural fingerprints. , 2011, Methods in molecular biology.

[31]  G. Hard,et al.  Mechanisms of Chemically Induced Renal Carcinogenesis in the Laboratory Rodent , 1998, Toxicologic pathology.

[32]  P. Working,et al.  Histopathology of acute toxic responses in selected tissues from rats exposed by inhalation to methyl bromide. , 1987, Fundamental and applied toxicology : official journal of the Society of Toxicology.

[33]  Worth Andrew,et al.  Review of QSAR Models and Software Tools for predicting Acute and Chronic Systemic Toxicity , 2010 .

[34]  J V de Julián-Ortiz,et al.  Predictability and prediction of lowest observed adverse effect levels in a structurally heterogeneous set of chemicals , 2005, SAR and QSAR in environmental research.

[35]  Emilio Benfenati,et al.  REACH and in silico methods: an attractive opportunity for medicinal chemists. , 2014, Drug discovery today.

[36]  M. Ohnishi,et al.  Mechanism of urinary tract crystal formation following biphenyl treatment. , 2001, Toxicology and applied pharmacology.

[37]  H. Greim.  Mechanistic and toxicokinetic data reducing uncertainty in risk assessment. , 2003, Toxicology letters.

[38]  Emilio Benfenati,et al.  A new in silico classification model for ready biodegradability, based on molecular fragments. , 2014, Chemosphere.

[39]  L. Babiss,et al.  Toxicogenomics in predictive toxicology in drug development. , 2004, Chemistry & biology.

[40]  Sunny Ohia,et al.  Naphthalene toxicity and antioxidant nutrients. , 2002, Toxicology.

[41]  E Benfenati,et al.  ToxRead: A tool to assist in read across and its use to assess mutagenicity of chemicals£ , 2014, SAR and QSAR in environmental research.

[42]  Xinxin Ding,et al.  Human extrahepatic cytochromes P450: function in xenobiotic metabolism and tissue-selective chemical toxicity in the respiratory and gastrointestinal tracts. , 2003, Annual review of pharmacology and toxicology.

[43]  Raffaella Corvi,et al.  The Assessment of Repeated Dose Toxicity In Vitro: A Proposed Approach , 2006, Alternatives to laboratory animals : ATLA.

[44]  M. Kriška,et al.  Risks of antibiotic treatment. , 2002, Bratislavske lekarske listy.

[45]  D. Barceló,et al.  Identification and determination of metabolites and degradation products of sulfonamide antibiotics , 2008 .

[46]  M. Ohnishi,et al.  Carcinogenicity of biphenyl in mice by two years feeding. , 2005, The Journal of veterinary medical science.

[47]  W. Kluwe.  Renal function tests as indicators of kidney injury in subacute toxicity studies. , 1981, Toxicology and applied pharmacology.

[48]  Brigitte Vollmar,et al.  Regulation of hepatic blood flow: the hepatic arterial buffer response revisited. , 2010, World journal of gastroenterology.

[49]  Domenico Gadaleta.  A k-NN algorithm for predicting oral sub-chronic toxicity in the rat - Supplementary Data , 2014 .

[50]  Roberto Todeschini,et al.  Handbook of Molecular Descriptors , 2002 .

[51]  G. L. Kedderis,et al.  Metabolism of chloroform by cytochrome P450 2E1 is required for induction of toxicity in the liver, kidney, and nose of male mice. , 1999, Toxicology and applied pharmacology.

[52]  I. Hakkinen,et al.  Electrophysiological findings in diphenyl poisoning , 2022 .

[53]  Hannu Raunio,et al.  In Silico Toxicology – Non-Testing Methods , 2011, Front. Pharmacol..

[54]  T. Ruml,et al.  Study of Cytotoxic Effects of Benzonitrile Pesticides , 2015, BioMed research international.

[55]  E Benfenati,et al.  Automatic knowledge extraction from chemical structures: the case of mutagenicity prediction , 2013, SAR and QSAR in environmental research.

[56]  R. S. Thomas,et al.  Comparative hepatocarcinogenicity of hexachlorobenzene, pentachlorobenzene, 1,2,4,5-tetrachlorobenzene, and 1,4-dichlorobenzene: application of a medium-term liver focus bioassay and molecular and cellular indices. , 2000, Toxicological sciences : an official journal of the Society of Toxicology.

[57]  M. Ohnishi,et al.  Two‐year Study of Carcinogenicity and Chronic Toxicity of Biphenyl in Rats , 2002 .

[58]  J. H. Smith,et al.  Mechanism of chloroform nephrotoxicity. III. Renal and hepatic microsomal metabolism of chloroform in mice. , 1984, Toxicology and applied pharmacology.

[59]  Emilio Benfenati,et al.  A K-nn Algorithm for Predicting the Oral Sub- Chronic Toxicity in the Rat , 2022 .