Dynamic model for selective metabolic activation in chemical carcinogenesis
Theoretical calculations predict the relative ease of formation of carbonium ions from 7,8-dihydro-7,8-dihydroxybenzo(a)pyrene-9,10-oxide or from either of the 2 symmetrical bay regions of B(e)P, and suggest their attraction to cellular nucleophiles. When both isomers were metabolized by hamster embryo fibroblasts (HEF) and the products analyzed, the results showed that the probable reason for benzo(e)pyrene's lack of carcinogenicity was its metabolic preference to attack the molecule away from the bay-region area. Particularly striking was the absence of any evidence for the formation of a significant amount of B(e)P-9,10-dihydrodiol. This suggests a metabolic basis for the relative lack of carcinogenic and mutagenic activity of B(e)P. The reason for this is not clear but may be due to physical or chemical factors such as membrane solubility or stereochemical requirements of the active site of the enzyme. The bay-region theory of PAH carcinogenesis predicts that carbonium ion formation from 9,10-dihydro-9,10-dihydroxybenzo(e)pyrene-11, 12-oxide, if formed, would be energetically favorable. Thus, the inability of HEF and microcomes to form B(e)P-9,10-dihydrodiol, the precursor of its potentially highly reactive diol-epoxide, would explain the relative inertness of B(e)P in several biological systems. As the subtle biochemical interactions of the various carcinogen intermediates become clarified, it becomes apparent that susceptibility and resistance to malignant transformation are based on a complex set of both chemical and physical parameters. It is becoming clear that metabolism kinetics, membrane interaction, and the role of nuclear metabolism help dictate the passage of the carcinogen and its reactive intermediates into and through the metabolic machinery of the cell. (ERB)
- Research Organization:
- Oak Ridge National Lab., TN (USA)
- DOE Contract Number:
- W-7405-ENG-26
- OSTI ID:
- 5059574
- Report Number(s):
- CONF-800498-3
- Resource Relation:
- Conference: Symposium on mutagenesis and carcinogenesis, Warsaw, Poland, 21 Apr 1980
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
59 BASIC BIOLOGICAL SCIENCES
BENZOPYRENE
METABOLITES
CARCINOGENESIS
BIOCHEMICAL REACTION KINETICS
CARCINOGENS
METABOLIC ACTIVATION
BIOLOGICAL PATHWAYS
EPOXIDES
EXPERIMENTAL DATA
FIBROBLASTS
GLYCOLS
MEMBRANE TRANSPORT
METABOLISM
ONCOGENIC TRANSFORMATIONS
STEREOCHEMISTRY
ALCOHOLS
ANIMAL CELLS
AROMATICS
CONDENSED AROMATICS
CONNECTIVE TISSUE CELLS
DATA
HYDROCARBONS
HYDROXY COMPOUNDS
INFORMATION
KINETICS
NUMERICAL DATA
ORGANIC COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
PATHOGENESIS
REACTION KINETICS
SOMATIC CELLS
560301* - Chemicals Metabolism & Toxicology- Cells- (-1987)
550200 - Biochemistry
550900 - Pathology
551000 - Physiological Systems