Comparative tumorigenicity of dimethylchrysenes in mouse skin

Abstract

In previous studies, we have observed unexpected structure-tumorigenicity relationships among the dimethylchrysenes. Thus, 5,6-dimethylchrysene and 5,7-dimethylchrysene were only weakly tumorigenic and were significantly less active than 5-methylchrysene. These results were surprising in view of the known route of metabolic activation of 5-methylchrysene via its 1,2-diol 3,4-epoxide. In this paper, we extended our studies of structure-tumorigenicity relationships among the dimethylchrysenes. We synthesized 5,7-, 5,8-, 5,9-, and 5,10-dimethylchrysene via photochemical ring closure reactions. The tumor-initiating activities of these dimethylchrysenes on mouse skin were compared with those of 5-methylchrysene and 5,6-dimethylchrysene. 5-Methylchrysene and 5,9-dimethylchrysene were highly tumorigenic and were significantly more active than 5,6-, 5,7-, 5,8-, and 5,10-dimethylchrysene. The results of these studies, taken together with those reported in the subsequent two papers, suggest that the molecular shapes of dimethylchrysenes influence the balance between metabolic activation and detoxification pathways.

Dimethylchrysenediol epoxides: mutagenicity in Salmonella typhimurium, tumorigenicity in newborn mice, and reactivity with deoxyadenosine in DNA

“…Proton NMR spectra were determined in CDC13 with a Bruker AM 360 WB spectrometer, unless noted otherwise. 1 Abbreviations: 5-MeC, 5-methylchrysene; 5,6-diMeC, 5,6-di methylchrysene; <mti-5-MeC-l,2-diol 3,4-epoxide, (±)-anti-l,2-di hydroxy-3,4-epoxy-l,2,3,4-tetrahydro-5-methylchrysene; anti-5,6-diMeC 1,2-diol 3,4-epoxide, (±)-anti-l,2-dihydroxy-3,4-epoxy-l,2,3,4-tetra hydro-5,6-dimethylchrysene; 5,6-diMeC-1,2-diol, 1,2-dihydro-1,2-di hydroxy-5,6-dimethylchrysene; 5,9-diMeC-l,2-dione, 5,9-dimethyl chrysene-1,2-dione; dG, deoxyguanosine; dA, deoxyadenosine; BcPh benzofcjphenanthrene; DMBA, 7,12-dimethylbenz[a]anthracene; BgC benzo [g]chrysene, THE, tetrahydrofuran; LAH, lithium aluminum hy dride; PCC, pyridinium chlorochromate; DMSO, dimethyl sulfoxide m-CPBA, m-chloroperoxybenzoic acid.…”

“…(A) anti-5,6-DiMeC-l,2-diol 3,4-Epoxide (8). (1) l-(3,4-Dimethyl-l-naphthyl)-2-(3-methoxyphenyl)ethylene (3). A mixture of l-(chloromethyl)-3,4-dimethylnaphthalene (5) (1.0 g, 5 mmol) and triphenylphosphine (1.31 g, 5 mmol) in benzene (100 mL) was heated at reflux for 6 h, cooled, and filtered to give the phosphonium salt 1 (1.3 g, 56.5%).…”

“…NaOMe (0.23 g, 4 mmol) was added to a solution of 1 (1.3 g, 3 mmol) and m-anisaldehyde (2, 0.4 g, 3 mmol) in MeOH (150 mL) at room temperature, and the mixture was stirred for 3 h. The contents were diluted with H20 (150 mL) and extracted with CH2C12. The organic layer was washed with H20, dried (MgS04), and concentrated in vacuo.…”

Integrating Field Analyses with Laboratory Exposures to Assess Ecosystems Health

“…Controls treated with solvent and TPA alone had a low incidence (0-10% ) of skin papillomas (Amin et al, 1985c;El-Bayoumy et al, 1986Amin et al, 1990Amin et al, , 1992.…”

“…(see also Table 3.2) Mouse Application of total initiating doses of 0-100 nmol and 0-1.5 µmol 5-methylchrysene to the skin of female CD-1 mice followed by thrice-weekly applications of 2.5 µg TPA significantly increased the incidence (65-100%) and multiplicity of skin papillomas. Controls treated with solvent and TPA alone had a low incidence (0-10% ) of skin papillomas (Amin et al, 1985c;El-Bayoumy et al, 1986Amin et al, 1990Amin et al, , 1992. …”