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.
Lewis
D F
DF
Molecular Toxicology Group, School of Biological Sciences, University of Surrey, Guildford, UK.
Ioannides
C
C
Parke
D V
DV
D000818:Animals; D015197:Carcinogenicity Tests / Q000379:methods*; D002273:Carcinogens / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000378:metabolism*; D004790:Enzyme Induction; D006801:Humans; D008055:Lipids / Q000737:chemistry; D015394:Molecular Structure; D009152:Mutagenicity Tests; D009369:Neoplasms / Q000139:chemically induced* / Q000453:epidemiology; D012995:Solubility; D013329:Structure-Activity Relationship
D002273:Carcinogens; D008055:Lipids; D003577:Cytochrome P-450 Enzyme System