Tumorigenicity of five dihydrodiols of benz(a)anthracene on mouse skin: exceptional activity of benz(a)anthracene 3,4-dihydrodiol.

Abstract

Benz[a anthracene and the five metabolically possible vicinal trans dilydrodiols of benz[ajanthracene were tested for ability to initiate skin tumors in CD-i female mice.A single topical a fication of 0.4-2.0 ,mol of hydrocarbon was followed 18 days later by twice weekly applications of the skin promoter 12-O-tetradecanoylphorbol-13-acetate. Comparisons of latency period, percent of mice with tumors, and number of papillomas observed per mouse indicated that benz[alanthracene 3,4-dihydrodiol was 10-to 20-fold more tumorigenic than the parent hydrocarbon, benz[aJanthracene. The nz[a anthracene 1,2-, 5,6-, 8,9-, and 10,11-dihydrodiols were all less active tumor initiators than was benz[aJanthracene. The high tumorigenicity of benzajanthracene 3,4dihydrodiol, presumably the result of metabolism to either or both of the diastereomeric benztalanthracene 3,4diol-1,2-epoxides, supports the bay region theory of polycyclic hydrocarbon carcinogenicity and provides the first example of a proximate carcinogenic metabolite that is much more active than the parent hydrocarbon on mouse skin.Highly active metabolic intermediates, designated ultimate carcinogens, are responsible for the carcinogenic activity of polycyclic-aromatic hydrocarbons and many other cancercausing chemicals (1-4). Benzo[a]pyrene 7,8-diol-9,10-epoxide appears to be the principal ultimate carcinogen of the polycyclic environmental pollutant benzo[a Ipyrene. This conclusion is based, in part, on DNA binding (5) and the exceptionally high mutagenicity of the diastereomeric benzo[a]pyrene 7,8-diol-9,10-epoxides (6-8), as well as the high carcinogenicity of one of these diastereomers (9). The two proximate metabolic precursors of the 7,8-diol-9,10-epoxide, benzo[a]pyrene 7,8-oxide (10), and trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (9, 11) have the requisite high carcinogenicity.The possibility that diol epoxides are responsible for the carcinogenicity of other polycyclic aromatic hydrocarbons is a subject of substantial importance. We have developed a general hypothesis to predict which diol epoxides of polycyclic hydrocarbons are the ultimate carcinogenic forms of the parent hydrocarbon (8,12,13). This hypothesis proposes that the formation of a bay regiont epoxide on a saturated, angular benzo-ring is a principal determinant of polycyclic hydrocarbon carcinogenicity. Application of the bay region theory to benz [a]anthracene (BA) predicts that 3,4-dihydroxy-1,2-epoxy-1,2,3,4-tetrahydrobenz[a]anthracene (BA 3,4-diol-1,2-epoxide) will have greater mutagenic and carcinogenic activity than other metabolically possible diol epoxides of benz [a]anthracene. Since dihydrodiol formation precedes epoxidation at the adjacent double bond, trans-3,4-dihydroxy-3,4-dihydrobenz[a]anthracene (BA 3,4-dihydrodiol) would be the critical metabolic precursor of the bay region diol epoxide of benz [a]anthracene. This proposal contrasts to the suggestion of Grover, Sims, and associates that the BA 8,9-diol-10,11-epoxide should have high biological activity and that...

The Bay-Region Theory of Carcinogenesis by Polycyclic Aromatic Hydrocarbons

“…7) were tested for their ability to initiate skin tumors in CD-I female mice (44). 7) were tested for their ability to initiate skin tumors in CD-I female mice (44).…”

The initiation of tumours on mouse skin by dihydrodiols derived from 7,12‐dimethylbenz(a)anthracene and 3‐methylcholanthrene

“…Such studies may also clearly show whether or not hydroxylation elsewhere in the molecule, i.e., at a methyl group or on a methylene bridge, is also involved, in addition to diol-epoxide formation, in the metabolic activation of carcinogenic polycyclic hydrocarbons like 7,12-dimethylbenz[a]anthracene and 3-methylcholanthrene. (Malaveille et a/., 1975; Wood ef a/., 19760,b) or as carcinogens (Chouroulinkov et al, 1976;Wood et a/., 1977;Wislocki et al, 1978) with the exception of the K-region dihydrodiol derived from dibenz(a,h)anthracene. This compound has been reported to be converted in the presence of microsomal mono-oxygenases and epoxide hydratase to a bacterial mutagen and on the basis of this evidence it has been proposed that a diol-epoxide derivative of the K-region diol was the active species formed (Wood et a/., 1978).…”

Drug Metabolism in the Skin

“…3) is regarded as the ultimate carcinogenic metabolite of benzo [a]pyrene. These findings are consistent with the so-called bay region theory which has been well established in skin for many PAH (BRESNICK et al 1977;BUENING et al 1980;CHANG et al 1982CHANG et al , 1983CHOUROuLINKovet al 1976CHOUROuLINKovet al , 1977CHOUROuLINKovet al , 1979HECHT et al 1980;LEVIN et al 1976aLEVIN et al , b, 1977aLEVIN et al , b, 1978aLEVIN et al , b, 1979LEVIN et al , 1980aSLAGA et al 1976SLAGA et al , 1977bSLAGA et al , d, 1978SLAGA et al , 1979aWISLOCKI et al 1977;WOOD et al 1977;for review see THAKKER et al 1985).…”