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

Chemistry Central Journal

Emilio Benfenati¹  Orazio Nicolotti²  Anna Lombardo¹  Domenico Gadaleta²  Fabiola Pizzo¹ 

[1]Laboratory of Environmental Chemistry and Toxicology, IRCCS-Istituto di Ricerche Farmacologiche “Mario Negri”, Via La Masa 19, Milan, 20159, Italy

[2]Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari “Aldo Moro”, Bari, Italy

关键词: Mechanism of action;    In silico;    Toxicity;    Structural alerts;    Kidney;    Liver;   

Others  :  1230617
DOI  :  10.1186/s13065-015-0139-7

 received in 2015-07-28, accepted in 2015-10-27,  发布年份 2015

【 摘 要 】

Background

The 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.

Results

We 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).

Conclusions

It 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.

【 授权许可】

   
2015 Pizzo et al.

【 图 表 】

Fig.1.

Fig.2.

Fig.3.

Fig.4.

【 参考文献 】

• [1]Abernethy DR, Woodcock J, Lesko LJ. Pharmacological mechanism-based drug safety assessment and prediction. Clin Pharmacol Ther. 2011; 89:793-797.
• [2]Roberts SM, James RC, Franklin MR. Hepatotoxicity: toxic effects on the liver. Principles of toxicology: environmental and industrial applications. Williams PL, James RC, Roberts SM, editors. Wiley, USA; 2010.
• [3]Eipel C, Abshagen K, Vollmar B. Regulation of hepatic blood flow: hepatic arterial buffer response revisited. World J Gastroentero. 2010; 16:6046-6057.
• [4]Hodgson E, Levi PE. Hepatotoxicity. In: A textbook of modern toxicology. Hodgson E, editor. Wiley, USA; 2004: p.2004.
• [5]Williams DP, Park BK. Idiosyncratic toxicity: the role of toxicophores and bioactivation. Drug Discov Today. 2003; 18:1044-1050.
• [6]Porter TD, Coon MJ. Cytochrome P-450. Multiplicity of isoforms, substrates, and catalytic and regulatory mechanisms. J Biol Chem. 1991; 266:13469-13472.
• [7]Ding X, Kaminsky LS. Human extrahepatic cytochromes P450: function in xenobiotic metabolism and tissue-selective chemical toxicity in the respiratory and gastrointestinal tracts. Ann Rev Pharmacol Toxicol. 2003; 43:149-173.
• [8]Cummings BS, Zangar RC, Novak RF, Lash LH. Cellular distribution of cytochromes P-450 in the rat kidney. Drug Met Dispos. 1999; 27:542-548.
• [9]Van Vleet TR, Schnellmann RG. Toxic nephropathy: environmental chemicals. Semin Nephrol. 2003; 23:500-508.
• [10]Fang C, Behr M, Xie F, Lu S, Doret M, Luo H, Yang W, Aldous K, Ding X, Gu J. Mechanism of chloroform-induced renal toxicity: non-involvement of hepatic cytochrome P450-dependent metabolism. Toxicol Appl Pharmacol. 2008; 227:48-55.
• [11]Hodgson E, Levi PE. Nephrotoxicity. A textbook of modern toxicology. 3rd ed. Hodgson E, editor. Wiley, USA; 2004.
• [12]Suter L, Babiss LE, Wheeldon EB. Toxicogenomics in predictive review toxicology in drug development. Chem Biol. 2004; 11:161-171.
• [13]Prieto P, Baird AW, Blaauboer BJ, Castell Ripoll JV, Corvi R, Dekant W, Dietl P, Gennari A, Gribaldo L, Griffin JL, Hartung T, Heindel JJ, Hoet P, Jennings P, Marocchio L, Noraberg J, Pazos P, Westmoreland C, Wolf A, Wright J, Pfaller W. The assessment of repeated dose toxicity in vitro: a proposed approach. ATLA. 2006; 34:315-341.
• [14]Lilienblum W, Dekant W, Gebel T, Hengstler JG, Kahl R, Kramer PJ, Schweinfurth H, Wollin KM. Alternative methods to safety studies in experimental animals: role in the risk assessment of chemicals under the new European Chemicals Legislation (REACH). Arch Toxicol. 2008; 82:211-236.
• [15]Sakuratani Y, Zhang H, Nishikawa S, Yamazaki K, Yamada T, Yamada J, Gerova K, Chankov G, Mekenyan O, Hayashi M. Hazard evaluation support system (HESS) for predicting repeated dose toxicity using toxicological categories. SAR QSAR Env Res. 2013; 24:351-363.
• [16]European Commission (2006) Regulation (EC) of No 1907/2006 of the European parliament and of the council 18 December 2006 concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH), establishing a European Chemicals Agency, amending Directive 1999/45/EC and repealing Council Regulation (EEC) No 793/93 and Commission Regulation (EC) No 1488/94 as well as Council Directive 76/769/EEC and Commission Directives 91/155/EEC, 93/67/EEC, 93/105/EC and 2000/21/EC
• [17]European Commission (2009) Regulation (EC) No 1223/2009 of the European parliament and of the council of 30 November 2009 on cosmetic products
• [18]Raunio H (2011) In silico toxicology-non-testing methods. Front Pharmacol 2: 33/1
• [19]Nicolotti O, Benfenati E, Carotti A, Gadaleta D, Gissi A, Mangiatordi GF, Novellino E. REACH and in silico methods: an attractive opportunity for medicinal chemists. Drug Discov Today. 2014; 19:1757-1768.
• [20]Vinken M. The adverse outcome pathway concept: a pragmatic tool in toxicology. Toxicol. 2013; 312:158-165.
• [21]Hewitt M, Enoch SJ, Madden JC, Przybylak KR, Cronin MT. Hepatotoxicity: a scheme for generating chemical categories for read-across, structural alerts and insights into mechanism(s) of action. Crit Rev Toxicol. 2013; 43:537-558.
• [22]Mazzatorta P, Estevez MD, Coulet M, Schilter B. Modeling oral rat chronic toxicity. J Chem Inf Model. 2008; 48:1949-1954.
• [23]De Julián-Ortiz JV, García-Domenech R, Gálvez L et al.. Predictability and prediction of lowest o.bserved adverse effect levels in a structurally heterogeneous set of chemicals. SAR QSAR Environ Res. 2005; 16:263-272.
• [24]García-Domenech R, de Julián-Ortiz JV, Besalú E. True prediction of lowest observed adverse effect levels. Mol Diversity. 2006; 10:159-168.
• [25]Gadaleta D, Pizzo F, Lombardo A, Carotti A, Escher SE, Nicolotti O, Benfenati E. A k-NN algorithm for predicting oral sub-chronic toxicity in the rat. ALTEX. 2014; 31:4-14.
• [26]Chavan S, Friedman R, Nicholls IA. Acute toxicity-supported chronic toxicity prediction: a k-nearest neighbor coupled read-across strategy. Int J Mol Sci. 2015; 16:11659-11677.
• [27]Todeschini R, Consonni V. Handbook of molecular descriptors. Wiley-VCH, Weinheim; 2000.
• [28]Floris M, Manganaro A, Nicolotti O, Medda R, Mangiatordi GF, Benfenati E. A generalizable definition of chemical similarity for read-across. J Cheminf. 2014; 6:39. BioMed Central Full Text
• [29]Willett P (2011) Similarity searching using 2D structural fingerprints. In: Bajorath J (ed) Chemoinformatics and computational chemical biology, vol 672. Humana Press, pp 133–158
• [30]Lapenna S, Fuart-Gatnik M, Worth A (2010) Review of QSAR models and software tools for predicting acute and chronic systemic toxicity. JRC Scientific and Technical Reports
• [31]Tsakovska I, Lessigiarska I, Netzeva T, Worth AP. A mini review of mammalian toxicity (Q)SAR models. QSAR Comb Sci. 2007; 27:41-48.
• [32]Gini G, Franchi AM, Manganaro A, Golbamaki A, Benfenati E. ToxRead: a tool to assist in read across and its use to assess mutagenicity of chemicals. SAR QSAR Environ Res. 2014; 25:999-1011.
• [33]Daylight, Chemical Information System Inc. http://www. daylight.com/dayhtml/doc/theory/theory.smarts.html webcite
• [34]Gustafson DL, Long ML, Thomas RS, Benjamin SA, Yang RSH. 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. Toxicol Sci. 2000; 53:245-252.
• [35]Greim H. Mechanistic and toxicokinetic data reducing uncertainty in risk assessment. Toxicol Lett. 2003; 138:1-8.
• [36]Cho TM, Rose RL, Hodgson E. In vitro metabolism of naphthalene by human liver microsomal cytochrome P450 enzymes. Drug Metab Dispos. 2006; 34:176-183.
• [37]Ahmed AAE, Fatani AJ. Protective effect of grape seeds proanthocyanidins against naphthalene-induced hepatotoxicity in rats. Saudi Pharma J. 2007; 15:38-47.
• [38]Stohs SJ, Ohia S, Bagchi D. Naphthalene toxicity and antioxidant nutrients. Toxicol. 2002; 180:97-105.
• [39]Rao GS, Pandya KP. Biochemical changes unduced by naphthalene after oral administration in albino rats. Toxicol Lett. 1981; 8:311-315.
• [40]Yamauchi T, Komura S, Yagi K. Serum lipid peroxide levels of albino rats administered naphthalene. Biochem Intern. 1986; 13:1-6.
• [41]Vuchetich PJ, Bagchi D, Bagchi M, Hassoun EA, Tang L, Stohs SJ. Naphthalene-induced oxidative stress in rats and the protective effects of vitamin E succinate. Free Rad Biol Med. 1996; 21:577-590.
• [42]Preuss R, Angerer J, Drexler H. Naphthalene-an environmental and occupational toxicant. Int Arch Occup Environ Health. 2003; 76:556-576.
• [43]Michałowicz J, Duda W. Phenols-sources and toxicity. Polish J Environ Stud. 2007; 16:347-362.
• [44]Thompson DC, Perera K, London R. Quinone methide formation from para isomers of methylphenol (cresol), ethylphenol, and isopropylphenol: relationship to toxicity. Chem Res Toxicol. 1995; 8:55-60.
• [45]Umeda Y, Arito H, Kano H, Ohnishi M, Matsumoto M, Nagano K, Yamamoto S, Matsushima T. Two-year study of carcinogenicity and chronic toxicity of biphenyl in rats. J Occup Health. 2002; 44:176-183.
• [46]Umeda Y, Aiso S, Arito H, Nagano K, Matsushima T. Induction of peroxisome proliferation in the liver of biphenyl-fed female mice. J Occup Health. 2004; 46:486-488.
• [47]Umeda Y, Aiso S, Yamazaki K, Ohnishi M, Arito H, Nagano K, Yamamoto S, Matsushima T. Carcinogenicity of biphenyl in mice by two years feeding. J VetMed Sci. 2005; 4:417-424.
• [48]Seppalainen AM, Hakkinen I. Electrophysiological findings in diphenyl poisoning. J Neurol Neurosur Psych. 1975; 38:248-252.
• [49]Carella G, Bettolo PM. Reversible hepatotoxic effects of diphenyl: report of a case and a review of the literature. J Occup Med. 1994; 36:575-576.
• [50]Hurtt ME, Morgan KT, Working PK. Histopathology of acute toxic responses in selected tissues from rats exposed by inhalation to methyl bromide. Fund Appl Toxicol. 1987; 9:352-365.
• [51]Ferrari T, Cattaneo D, Gini G, Golbamaki Bakhtyari N, Manganaro A, Benfenati E. Automatic knowledge extraction from chemical structures: the case of mutagenicity prediction. SAR QSAR Environ Res. 2013; 24:365-383.
• [52]Garcıa-Galan MJ, Dıaz-Cruz MS, Barcelo D. Identification and determination of metabolites and degradation products of sulfonamide antibiotics. Trends Anal Chem. 2008; 27:11.
• [53]Chen J, Zhou X, Zhang Y, Gao H. Potential toxicity of sulfanilamide antibiotic: binding of sulfamethazine to human serum albumin. STOTEN. 2012; 432:269-274.
• [54]Perazella MA. Crystal-induced Acute Renal Failure. Am J Med. 1999; 106:459-465.
• [55]Wawruch M, Bozekova L, Krcmery S, Kriska M. Risks of antibiotic treatment. Brat Med J. 2002; 103:270-275.
• [56]Holtze MS, Sørensen SR, Sørensen J, Aamand J. Microbial degradation of the benzonitrile herbicides dichlobenil, bromoxynil and ioxynil in soil and subsurface environments e Insights into degradation pathways, persistent metabolites and involved degrader organisms. Environ Poll. 2008; 154:155-168.
• [57]Lovecka P, Thimova M, Grznarova P, Lipov J, Knejzlik Z, Stiborova H, Gde T, Nindhia T, Demnerova K, RumlT (2015) Study of cytotoxic effects of benzonitrile pesticides. BioMed Res Internat (Article ID 381264)
• [58]Smith JH, Hook JB. Mechanism of chloroform nephrotoxicity III. Renal and hepatic microsomal metabolism of chloroform in mice. Toxicol Appl Pharmacol. 1984; 73:511-524.
• [59]Branchplower RV, Nunn DS, Highet RJ, Smith JH, Hook JB, Pohl LR. Nephrotoxicity of chloroform: metabolism to phosgene by the mouse kidney. Toxicol Appl Pharmacol. 1984; 72:159-168.
• [60]Hard G. Mechanisms of chemically induced renal carcinogenesis laboratory rodent. Toxicol Pathol. 1998; 26(101–1):12.
• [61]Constan AA, Sprankle CS, Peters JM, Kedderis GL, Everitt JI, Wong BA, Gonzalez FL, Butterworth BE. Metabolism of chloroform by cytochrome P450 2E1 is required for induction of toxicity in the liver, kidney, and nose of male mice. Toxicol Appl Pharmacol. 1999; 160:120-126.
• [62]Booth A, Ambrose AM, Deeds F, Cox AJ. The reversible nephrotoxic effects of biphenyl. Toxicol Appl Pharmacol. 1961; 3:560-567.
• [63]Kluwe WM. Renal function tests as indicators of kidney injury in subacute toxicity studies. Toxicol Appl Pharmacol. 1981; 57:414-424.
• [64]Ohnishi M, Yajima Y, Yamamoto S, Matsushima T, Ishii T. Sex dependence of the components and structure of urinary calculi induced by biphenyl administration in rats. Chem Res Toxicol. 2000; 13:727-735.
• [65]Ohnishi M, Yajima H, Takeuchi T, Saito M, Yamazaki K, Kasai T, Nagano K, Yamamoto S, Matsushima T, Ishii T. Mechanism of urinary tract crystal formation following biphenyl treatment. Toxicol Appl Pharmacol. 2001; 174:122-129.
• [66]Marchant CA, Fisk L, Note RR, Patel ML, Suarez D. An expert system approach to the assessment of hepatotoxic potential. Chem Biodiver. 2009; 6:2107-2114.
• [67]EOCD QSAR toolbox. http://www.qsartoolbox.org/. Accessed 23 July 2015
• [68]PubChem compound website. https://pubchem.ncbi.nlm.nih.gov/. Accessed 23 July 2015
• [69]ChemID plus. http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 23 July 2015
• [70]Lombardo A, Pizzo F, Benfenati E, Manganaro A, Ferrari T, Gini G. A new in silico classification model for ready biodegradability, based on molecular fragments. Chemosphere. 2014; 108:10-16.