Restricted accessResearch articleFirst published online 1998-10
A combined COMPACT and HazardExpert study of 40 chemicals for which information on mutagenicity and carcinogenicity is known,including the results of human epidemiological studies
The COMPACT approach for defining structural criteria for substrates and inducers of cytochrome P450 (CYP) enzymes which mediate the formation of reactive intermediates is discussed in the context of prediction of potential carcinogenicity. This is broadened to encompass structural studies on mammalian P450s, including those relevant to genetic polymorphism in man. The use of the COMPACT system, in parallel with the structure alert program HazardExpert (now incorporated into the Pallas system), for evaluating human carcinogenicity data is reported, as an example of the possible employment of a battery of short-term test procedures for safety evaluation. In particular, the importance of using the log P value (as a measure of compound lipophilicity) to assess the likelihood of a potentially toxic compound reaching the site of activation, is emphasized by the finding that most procarcinogens requiring metabolic activation by P450s are lipophilic in nature.
Porter TD , Coon MJ.Cytochrome P-450: multiplicity of isoforms, substrates and catalytic and regulatory mechanisms . Journal of Biological Chemistry1991; 266: 13469-13472 .
2.
Guengerich FP , Shimada T.Oxidation of toxic and carcinogenic chemicals by human cytochrome P450 enzymes . Chemical Research in Toxicology1991; 4: 391-407 .
3.
Rendic S , Di Carlo FJ.Human cytochrome P450 enzymes: a status report summarizing their reactions, substrates, inducers and inhibitors . Drug Metabolism Reviews1997; 29: 413-580 .
4.
Vermeulen NPE . Role of metabolism in chemical toxicity, In: Cytochromes P450: Metabolic and Toxicological Aspects; C Ioannides (ed.) CRC Press, Boca Raton, Florida1996; Ch. 2, 29-53.
5.
Guengerich FP.Roles of cytochrome P-450 enzymes in chemical carcinogenesis and cancer chemotherapy . Cancer Research1988; 48: 2946-2954 .
6.
Ioannides C , Lewis DFV , Parke DV.Mechanisms of chemical carcinogenesis and molecular parametric analysis in the safety evaluation of chemicals, In: Drugs, Diet and Disease, Volume 1: Mechanistic Approaches to Cancer; C. Ioannides and DFV Lewis , (eds) 1995. Chichester: Ellis Horwood , 1-46.
7.
Guengerich FP.Human cytochrome P450 enzymes, In: Cytochrome P450 . PR Ortiz de Montellano (ed.) Plenum, New York1995. Ch.14, 474-535.
8.
Shimada T , et al.Inter-individual variations in human liver cytochrome P450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals . Journal of Pharmacology and Experimental Therapeutics1994; 270: 414-423 .
9.
Gibson GG , Skett P.Introduction of Drug Metabolism, Chapman & Hall, London . 1994.
10.
Lewis DFV , Ioannides C , Parke DV.Molecular dimensions of the substrate binding site of cytochrome P-448 . Biochemical Pharmacology1986; 35: 2179-2185 .
11.
Lewis DFV , Ioannides C , Parke DV.Structural requirements for substrates of cytochromes P-450 and P-448 . Chemico-Biological Interactions1987; 64: 39-60 .
12.
Lewis DFV , Ioannides C , Parke DV.Prediction of chemical carcinogenicity from molecular and electronic structure: A comparison of MINDO/3 and CNDO/2 molecular orbital methods . Toxicology Letters1989; 45: 1-13 .
13.
Lewis DFV , Ioannides C , Parke DV.The safety evaluation of drugs and chemicals by the use of computer optimized molecular parametric analysis of chemical toxicity (COMPACT) . Alternatives to Laboratory Animals1990; 18: 91-102 .
14.
Lewis DFV.Computer modelling of cytochromes P-450 and their substrates: A rational approach to the prediction of carcinogenicity . Frontiers in Biotransformation1992; 7: 90-136 .
15.
Lewis DFV , et al.Molecular modelling of enzymes and receptors involved in carcinogenesis: QSARs and COMPACT-3D . Drug Metabolism Reviews1994; 26: 261-285 .
16.
Lewis DFV , Ioannides C , Parke DV.Validation of a novel molecular orbital approach (COMPACT) to the safety evaluation of chemicals by comparison with Salmonella mutagenicity and rodent carcinogenicity data evaluated by the US NCI/NTP . Mutation Research1993; 291: 61-77 .
17.
Lewis DFV , Ioannides C , Parke DV.Further validation of COMPACT, the molecular orbital approach for the prospective evaluation of chemicals; re-evaluation of 200 miscellaneous chemicals by comparison with rodent carcinogenicity and salmonella mutagenicity data from the US NCI/NTP . Mutation Research1998; 412: 41-54 .
18.
Brown SJ , Raja AA , Lewis DFV.A comparison between COMPACT and HazardExpert evaluations for 80 chemicals tested by the NTP/NCI rodent bioassay . ATLA1994; 22: 482-500 .
19.
Lewis DFV , Ioannides C , Parke DV.COMPACT and molecular structure in toxicity assessment: A prospective evaluation of 30 chemicals currently being tested for rodent carcinogenicity by the National Toxicology Program . Environmental Health Perspectives1996; 104: 1011-1016 .
20.
Lewis DFV , Langley GR.A validation of the COMPACT and HazardExpert techniques with 40 chemicals . Mutation Research1995; 369: 157-174 .
21.
Lewis DFV , Ioannides C , Parke DV.A retrospective evaluation of COMPACT predictions of rodent carcinogenicity testing from the NTP rodent bioassay results of 40 chemicals . Environmental Health Perspectives1995; 103: 178-184 .
22.
Lewis DFV , Ioannides C , Parke DV.A retrospective study of the molecular toxicology of benoxaprofen . Toxicology1991; 65: 33-47 .
23.
Ayrton AD , Ioannides C , Parke DV.Induction of the cytochrome P450I and IV families and peroxisomal proliferation in the liver of rats treated with benoxaprofen. Possible implications in its hepatotoxicity . Biochemical Pharmacology1991; 42: 109-115 .
24.
Roffey SJ. Structure-activity relationships in the metabolism of a series of tertiary amines by cytochrome P450. Ph.D. Thesis, University of Surrey, Guildford, Surrey, UK. 1993.
25.
Lewis DFV , Lake BG.Molecular modelling of mammalian CYP2B isoforms and their interaction with substrates, inhibitors and redox partners . Xenobiotica1997; 27: 443-478 .
26.
Lewis DFV.Quantitative structure-activity relationships in substrates, inducers and inhibitors of cytochrome P450I . Drug Metabolism Reviews1997; 29: 589-650 .
27.
Lewis DFV.Three dimensional models of human and other mammalian microsomal P450s constructed from an alignment with P450102 (P450bm3) . Xenobiotica1995; 25: 333-336 .
28.
Lewis DFV.Cytochromes P450: Structure, Function and Mechanism1996. Taylor & Francis, London .
29.
Lewis DFV.The CYP2 family: models, mutants and interactions . Xenobiotica1998; 28: in press.
30.
Lewis DFV , Lake BG.Molecular modelling of members of the P4502A subfamily: application to studies of enzyme specificity . Xenobiotica1995; 25: 585-598 .
31.
Lewis DFV , Ioannides C , Parke DV.Molecular modelling of mammalian cytochromes P450 and evaluation of chemical toxicity and metabolism using COMPACT. In: QSAR and Molecular Modelling; F Sanz , J Giraldo , F Manaut (eds.) 1995; Prous, Barcelona , 595-600.
32.
Lewis DFV , Bird MG , Parke DV.Molecular modelling of CYP2E1 enzymes from rat, mouse and man: an explanation for the species differences in butadiene metabolism and rationalization of CYP2E substrate specificity . Toxicology1997; 118: 93-113 .
33.
Smith DA , Ackland MJ , Jones BC.Properties of cytochrome P450 isozymes and their substrates: Parts 1 and 2 . Drug Discovery Today1997; 2: 406-411 and 479-486 .
34.
Lewis DFV.Molecular modelling, In: Food Chemical Risk Analysis, DR Tennant (ed.) Blackie, London1997; Ch. 7, 163-194.
35.
Lewis DFV , Lake BG.Quantitative structure-activity relationship (QSAR) analysis for a series of rodent peroxisome proliferators: interaction with the mouse liver peroxisome proliferator-activated receptor a (mPPARa) . Toxicology in Vitro1997; 11: 99-105 .
36.
Ennever FK , Noonan TJ , Rosenkranz HS.The predictivity of animal bioassays and short-term genotoxicity tests for carcinogenicity and noncarcinogenicity to humans . Mutagenesis1987; 2: 73-78 .
37.
Stoloff L.An analysis of the 1987 list of IARC identified human carcinogens and the correlated animal studies . Regulatory Toxicology and Pharmacology1992; 15: 10-13 .
38.
Ashby J , Tennant RW.Definitive relationships among chemical structure, carcinogenicity and mutagenicity for 301 chemicals tested by the U.S. NTP , Mutation Research1991; 257: 229-306 .
39.
Vinter JG , Davis A , Saunders MR.Strategic approaches to drug design. I. An integrated software framework for molecular modelling . Journal of Computer-Aided Molecular Design1987; 1: 31-51 .
40.
Parke DV , Ioannides C.Roles of cytochromes P450 in mouse liver tumour production.. In: Mouse Liver Carcinogenesis Mechanisms and Species Comparisons. Stevenson DE , et al. (eds); 1990; Alan Liss, New York , pp. 215-230.
41.
Lewis DFV.Comparison between rodent carcinogenicity test results of 44 chemicals and a number of predictive systems . Regulatory Toxicology and Pharmacology1994; 20: 215-222 .
42.
Purdy R.A mechanism-mediated model for carcinogenicity: model content and prediction of the outcome of rodent carcinogenicity bioassays currently being conducted on 25 chemicals . Environmental Health Perspectives1996; 104: 1085-1094 .
43.
Purdy R.A hierarchical QSAR model for predicting carcinogenicity . International Laboratory News1997; June issue, 16-16 .
44.
Lewis DFV. , Ioannides C. , and Parke DV.An improved version of the COMPACT procedure for the evaluation of P450-mediated chemical activation . Drug Metabolism Reviews, 1998; 30: in press.
