Inhibitory effects of 6-phenylhexyl isothiocyanate on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone metabolic activation and lung tumorigenesis in rats

Abstract

This study examined the effects of 6-phenylhexyl isothiocyanate (PHITC) on lung tumorigenesis in F344 rats induced by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Two biomarkers of NNK metabolism, 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB)-releasing hemoglobin adducts and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronide (NNAL-Gluc) in urine, were also quantified during the course of the tumor induction experiment. Rats were divided into groups as follows: (1) NNK, 2 p.p.m. in drinking water, 60 rats; (2) NNK, 2 p.p.m. in drinking water and PHITC, 1 micromol/g NIH-07 diet, 60 rats; (3) PHITC, 1 micromol/g NIH-07 diet, 20 rats; (4) control, 20 rats. PHITC was added to the diet for 1 week prior to and during 111 weeks of NNK treatment. There were no effects of PHITC on body weight, mortality, blood chemistry or hematology. Seventy percent of the rats treated with NNK had adenoma or adenocarcinoma of the lung. In the rats treated with NNK plus PHITC, the total percent incidence of lung tumors was 26% (P < 0.01 compared with NNK). PHITC had no effect on the total incidence of exocrine pancreatic tumors induced by NNK. The rats treated with PHITC and NNK had significantly lower levels of HPB-releasing hemoglobin adducts throughout the course of the bioassay than did those treated with NNK alone and significantly higher levels of NNAL plus NNAL-Gluc excreted in urine at two time points during the bioassay. These results demonstrate that near lifetime administration of PHITC to rats strongly inhibits the metabolic activation and lung tumorigenicity of NNK.

Biologic damage resulting from exposure to tobacco smoke and from radon: implication for preventive interventions

“…This was shown in a small controlled trial of 11 smokers who ate watercress (nasturtium officinale) with a minimum PEITC consumption averaging 19 -38 mg/day. The metabolic activation of NNK into carcinogenic metabolites was inhibited as observed by increased levels of detoxified metabolites excreted in urine (Hecht et al, 1995).…”

Identification of Critical Amino Acid Residues of Human Cyp2a13 for the Metabolic Activation of 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone, a Tobacco-Specific Carcinogen

“…During the metabolic activation, both the methyl and methylene carbons of NNK can be hydroxylated, leading to the formation of 4-oxo-4-(3-pyridyl)-1-butanone (keto alcohol) and 4-oxo-1-(3-pyridyl)-1-butanone (keto aldehyde), respectively, as well as the DNA-methylating and -pyridyloxobutylating species (Hecht et al, 1993a;Wang et al, 2003b). Several cytochrome P450 (P450) enzymes have been reported to be involved in the metabolic activation of NNK (Hecht et al, 1996;Patten et al, 1996;Felicia et al, 2000;Schrader et al, 2000;Su et al, 2000;Fujita and Kamataki, 2001;Jalas et al, 2003). However, there is a significant difference in the catalytic efficiency for NNK ␣-hydroxylation among these P450 enzymes.…”

Tobacco nitrosamines as culprits in disease: mechanisms reviewed

“…In support of these observations, keto alcohol-releasing adducts were formed by treatment of hemoglobin with NNK or NNKOAc [63]. In addition, reductions in keto alcohol-releasing product effectuated by treatment with phenethyl isothiocyanate significantly reduced NNK-mediated lung tumorigenesis [33]. Although hemoglobin keto alcohol-releasing adducts could potentially serve as non-invasive biomarkers of cancer risk in people exposed to NNK/tobacco smoke, their exceedingly low levels in smokers render this goal challenging for the near future.…”