Inhibition of NNK-induced lung tumorigenesis by modulators of NNK activation.
NNK, a tobacco-specific nitrosamine, is a potent lung carcinogen in A/J mice. One possible mechanism of reducing NNK-induced lung tumorigenesis is decreased delivery of NNK to lung as a result of enhanced hepatic CYP activity. Pretreatment with 13C, a known CYP inducer, results in inhibition of tumor multiplicity, decreased DNA adducts in lung, and increased DNA adducts in liver, due to induction of hepatic activation of NNK. A more preferable means of inhibition of NNK tumorigenesis involves direct inhibition of CYP enzymes responsible for NNK activation in lung. The arylalkyl isothiocyanates PEITC, PPITC, PBITC, PPeITC, and PHITC are effective inhibitors of NNK-induced lung tumorigenicity and DNA adduction. PEITC inhibits NNK-induced lung tumors at a dose of 5 mumol/day, but not at doses of 1 or 0.2 mumol/day. PPITC, PBITC, PPeITC, and PHITC are considerably more potent inhibitors than PEITC, resulting in significant reductions in tumor multiplicity at doses of 0.2 mumol/day. For these compounds, there is a good correlation between inhibition of tumor multiplicity and inhibition of pulmonary O6-methylguanine. LIM, previously shown by Wattenberg to be an effective inhibitor of NNK-induced lung tumors, and other monoterpenes are good inhibitors of NNK activation in vitro or in vivo. Thus, compounds that modulate the metabolic activation of NNK can be potent inhibitors of NNK tumorigenesis.
Morse
M A
MA
Division of Environmental Health Sciences, Ohio State University School of Public Health, Columbus, USA.
D000236:Adenoma / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D002273:Carcinogens / Q000378:metabolism / Q000633:toxicity*; D053138:Cyclohexenes; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D005260:Female; D007211:Indoles / Q000494:pharmacology; D017879:Isothiocyanates / Q000494:pharmacology; D000077222:Limonene; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D008175:Lung Neoplasms / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008805:Mice, Inbred A; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009602:Nitrosamines / Q000378:metabolism / Q000633:toxicity*; D013729:Terpenes / Q000494:pharmacology
D016588:Anticarcinogenic Agents; D002273:Carcinogens; D053138:Cyclohexenes; D065607:Cytochrome P-450 Enzyme Inhibitors; D007211:Indoles; D017879:Isothiocyanates; D009602:Nitrosamines; D013729:Terpenes; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D003577:Cytochrome P-450 Enzyme System; D000077222:Limonene; C016517:indole-3-carbinol