Carcinogenicity and mutagenicity of the 3,4-dihydrodiols and other metabolites of 7,12-dimethylbenz(a)anthracene and its hydroxymethyl derivatives.

نویسندگان

  • P G Wislocki
  • K M Gadek
  • M W Chou
  • S K Yang
  • A Y Lu
چکیده

Thirty-nine derivatives of 7,12-dimethylbenz(a)anthracene (DMBA) were tested for mutagenicity towards Salmonella typhimurium strain TA100 in the presence of activating enzymes. The compounds tested included four sets of 3,4-, 5,6-, 8,9-, and 10,11-diols: those of DMBA, its 7and 12-hydroxymethyl derivatives, and the 7,12-dihydroxymethyl derivative. Several phenolic derivatives and formyl and carboxylic acid derivatives at the 7 and 12 positions of DMBA were also tested. At the concentrations examined, only the 3,4-diols of DMBA and 7hydroxymethyl-12-methylbenzanthracene (7-OHM-12-MBA) were strongly mutagenic. These two 3,4-dihydrodiols were of equal mutagenicity. When DMBA, its three hydroxymethyl derivatives, and their respective dihydrodiols were tested for tumor-initiating activity in the mouse skin two-stage tumorigenesis model, the 3,4-diol of DMBA was the most potent initiator, causing a tumor inci dence after 23 weeks of promotion of 9.8 papillomas/mouse at a dose of 3 nmol/mouse. At this same dose level, the equally mutagenic 3,4-diol of 7-OHM-12-MBA caused a tumor inci dence of only 0.9 papillomas/mouse, while 7-OHM-1 2-MBA caused only 0.26 papillomas/mouse. The other metabolites tested were less tumorigenic than DMBA, which caused a tumor incidence of 2.9 papillomas/mouse at a dose of 3 nmol/ mouse. Therefore, the 3,4-diol of DMBA qualifies as a proxi mate carcinogen of DMBA and indicates that the bay-region 3,4-diol-1,2-epoxide of DMBA is probably an ultimate carcin ogen of DMBA in mouse skin. The 3,4-diol of 7-OHM-12-MBA, although not a proximate carcinogen of DMBA, appears to be a proximate carcinogen of 7-OHM-12-MBA and may therefore contribute to some of the carcinogenicity observed with DMBA through this hydroxymethyl derivative. The data also indicate the lack of a quantitative agreement between mutagenicity and carcinogenicity under the conditions of the tests used.

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عنوان ژورنال:
  • Cancer research

دوره 40 10  شماره 

صفحات  -

تاریخ انتشار 1980