Quantitative structure carcinogenicity relationship for detecting structural alerts in nitroso-compounds

Journal Article · Fri Jun 01 04:00:00 EDT 2007 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2007.02.021· OSTI ID:20976947

Helguera, Aliuska Morales ^[1]; Gonzalez, Maykel Perez ^[2]; Perez, Miguel Angel Cabrera ^[3]

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1. Department of Chemistry, Faculty of Chemistry and Pharmacy, Central University of Las Villas, Santa Clara, 54830, Villa Clara (Cuba)
2. Department of Drug Design, Chemical Bioactive Center, Central University of Las Villas, Santa Clara, 54830, Villa Clara (Cuba) and Department of Organic Chemistry, Vigo University, C.P. 36200, Vigo (Spain)
3. Department of Drug Design, Chemical Bioactive Center, Central University of Las Villas, Santa Clara, 54830, Villa Clara (Cuba)

Prevention of environmentally induced cancers is a major health problem of which solutions depend on the rapid and accurate screening of potential chemical hazards. Lately, theoretical approaches such as the one proposed here - Quantitative Structure-Activity Relationship (QSAR) - are increasingly used for assessing the risks of environmental chemicals, since they can markedly reduce costs, avoid animal testing, and speed up policy decisions. This paper reports a QSAR study based on the Topological Substructural Molecular Design (TOPS-MODE) approach, aiming at predicting the rodent carcinogenicity of a set of nitroso-compounds selected from the Carcinogenic Potency Data Base (CPDB). The set comprises nitrosoureas (14 chemicals), N-nitrosamines (18 chemicals) C-nitroso-compounds (1 chemical), nitrosourethane (1 chemical) and nitrosoguanidine (1 chemical), which have been bioassayed in male rat using gavage as the route of administration. Here we are especially concerned in gathering the role of both parameters on the carcinogenic activity of this family of compounds. First, the regression model was derived, upon removal of one identified nitrosamine outlier, and was able to account for more than 84% of the variance in the experimental activity. Second, the TOPS-MODE approach afforded the bond contributions - expressed as fragment contributions to the carcinogenic activity - that can be interpreted and provide tools for better understanding the mechanisms of carcinogenesis. Finally, and most importantly, we demonstrate the potentialities of this approach towards the recognition of structural alerts for carcinogenicity predictions.

• OSTI ID: 20976947
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 2 Vol. 221; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
CARCINOGENESIS
COST
DESIGN
FORECASTING
HEALTH HAZARDS
NEOPLASMS
NITROSAMINES
NITROSOUREAS
RATS
STRUCTURE-ACTIVITY RELATIONSHIPS
TESTING
TOPOLOGY