Effects of 3H-1,2-dithiole-3-thione, 1,4-phenylenebis(methylene)selenocyanate, and selenium-enriched yeast individually and in combination on benzo[a]pyrene-induced mutagenesis in oral tissue and esophagus in lacZ mice.
We have studied the effects of three chemopreventive agents alone or in binary combinations on benzo[a]pyrene (BaP)-induced mutagenesis in the oral cavity and esophagus of lacZ mice using galE(-) selection. The mice were fed diets supplemented with 1,4-phenylenebis(methylene)selenocyanate (p-XSC) at 2.5 and 10 ppm Se, selenium-enriched yeast (SeY) at 2.5 and 10 ppm Se, and 3H-1,2-dithiole-3-thione (D3T) at 65 and 250 ppm, for 6 weeks. Two weeks after the start of the dietary regimen, mice were gavaged with five doses of 125 mg/kg BaP over 2 weeks, and the experiment was terminated 2 weeks later. Mutagenesis was measured in tongue, other pooled oral tissues (OTs), and esophagus. In mice treated with BaP alone, mutagenesis in the above tissues was in the range of 21-32 mutants/10(5)pfu (ca. 6-10 background levels for the corresponding tissues). p-XSC modestly inhibited mutagenesis (10-33% inhibition) in all tissues, but statistical significance was only observed at the low dose in esophagus, and pooled OT. SeY was not inhibitory alone. Greater inhibitory effects were observed with D3T, and inhibition was statistically significant at the high dose in tongue and esophagus (ca. 33%). Two combinations of low doses of the inhibitors were tested, and the D3T + SeY mix was most effective, leading to statistically significant inhibition in all three tissues (ca. 30-40% inhibition). The mixture D3T + p-XSC was of similar effectiveness as the low dose of D3T alone. This study combined with those previously done in our laboratory demonstrates effectiveness of D3T and to a lesser extent, p-XSC in the inhibition of mutagenesis, and provides support for the use of certain combinations of inhibitors as a means to increase effectiveness and reduce the dose of chemopreventive agents.
Guttenplan
Joseph B
JB
Division of Basic Sciences/Biochemistry, New York University, Dental Center, New York, NY 10100, USA. joseph.guttenplan@nyu.edu
Spratt
Thomas E
TE
Khmelnitsky
Michael
M
Kosinska
Wieslawa
W
Desai
Dhimant
D
El-Bayoumy
Karam
K
D000818:Animals; D016587:Antimutagenic Agents / Q000494:pharmacology*; D001564:Benzo(a)pyrene; D004247:DNA / Q000302:isolation & purification; D004338:Drug Combinations; D004947:Esophagus / Q000187:drug effects*; D008297:Male; D051379:Mice; D016296:Mutagenesis / Q000187:drug effects*; D009152:Mutagenicity Tests; D016566:Organoselenium Compounds / Q000633:toxicity*; D012643:Selenium / Q000378:metabolism / Q000494:pharmacology*; D013871:Thiones / Q000633:toxicity*; D013876:Thiophenes / Q000633:toxicity*; D014059:Tongue / Q000187:drug effects*; D015003:Yeasts / Q000378:metabolism
D016587:Antimutagenic Agents; D004338:Drug Combinations; D016566:Organoselenium Compounds; D013871:Thiones; D013876:Thiophenes; D001564:Benzo(a)pyrene; C074153:1,4-phenylenebis(methylene)selenocyanate; D004247:DNA; D012643:Selenium; C049325:1,2-dithiol-3-thione