AN EXAMINATION OF DISTRIBUTION, MACROMOLECULAR BINDING, AND DNA ADDUCT FORMATION OF 7,12-DIMETHYLBENZ(A)ANTHRACENE IN SENCAR AND BALB/C MICE

MARK ANDREW MORSE, Purdue University

Abstract

The initiation-promotion assay in mice is a promising short-term in vivo test useful in examining the tumorigenicity of suspect compounds. When polycyclic aromatic hydrocarbons (PAHs) are used as initiators, the tumorigenic efficiency of this assay can vary tremendously, depending on the murine strain or stock and the route of administration employed. Balb/c mice are more resistant to epidermal tumor formation than SENCAR mice when either benzo(a)pyrene or 7,12-dimethylbenz(a)anthracene (DMBA) is used as the initiator. In such assays, topical administration is vastly more efficient in the production of murine epidermal tumors than other routes of administration, particularly the oral route. As these strain/stock and route differences in susceptibility to epidermal tumor formation might be due to differences in the initiation stage, the distribution and macromolecular binding of DMBA were examined in SENCAR and Balb/c mice after topical or oral administration. The formation of individual DMBA:DNA adducts was also examined. The availability and macromolecular binding of ('3)H-DMBA equivalents were found to be vastly greater in the skin or epidermis of mice administered DMBA topically than orally. Such phenomena may be the cause of the known differences in efficiency of epidermal tumor production obtained by these two routes. Although some differences were found between SENCAR and Balb/c mice in the distribution and macromolecular binding of DMBA, these differences could not account for the greater sensitivity of the SENCAR mouse. No substantial differences in the quantities or proportions of the major DMBA:deoxyribonucleoside adducts in epidermis (the anti-DMBA bay-region diol epoxide adducts of deoxyguanosine and deoxyadenosine, and a syn-DMBA bay-region diol epoxide:deoxyadenosine adduct) were found between SENCAR and Balb/c mice, although the proportions of the individual adducts did vary with time in both SENCAR and Balb/c mice. Hence, the above results indicate that differences in the initiation stage are not responsible for the exquisite sensitivity of SENCAR mice to PAH-induced epidermal tumorigenesis.

Degree

Ph.D.

Subject Area

Pharmacology

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