Metabolism and Carcinogenesis

of NNK and NNAL

 

 

 

The metabolites of nicotine--NNK and NNAL--pose a real threat to human health. It is these two compounds that make nicotine dangerous, due to fact that they are potent carcinogens specific to lung tissue. The following diagrams illustrate the pathways of metabolism of these compounds, NNK and NNAL.

 

NNK Metabolism --The metabolism of NNK can take 4 main paths: (1) detoxification to NNK-N-oxide, (2) hydroxylation at the methyl carbon, (2) hydroxylation at the methylene carbon, and (3) rapid conversion to 4(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), which has also been determined to be a potent carcinogen in rodents. alpha-hydroxylation is required to activate both NNK.

(1) Detoxification pathways will be discussed in a later section.

(2) NNK is hydroxylated at the methyl carbon next to the nitroso group, followed by formation of diazohydroxide. It diazohydroxide that is capable of pyridyloxobutylating DNA.

(3) Hydroxylation at the methylene carbon of NNK ultimately yields methanediazohydroxide, which can methylate DNA.

(4) Conversion to NNAL is followed by metabolism of NNAL as described in the next section.

 

NNAL Metabolism -- Like NNK, NNAL also requires a-hydroxylation to become metabolically active. Hydroxylation at the methyl and methylene carbons of NNAL results in similar metabolic intermediates to those formed from NNK. Once again, 4 main pathways for NNAL metabolism exist: (1) detoxification to NNAL-N-oxide, (2) detoxification to NNAL-Gluc, (3) hydroxylation at the methyl carbon, and (4) hydroxylation at the methylene carbon.

(1) & (2) Detoxification pathways will be discussed in a later section.

(3) alpha-hydroxylation of the methyl group of NNAL produces a DNA pyridylhydroxybutylating intermediate, which plays an important role in NNAL/NNK carcinogenicity

(4) Hydroxylation of the methylene group of NNAL yields 5-(3-pyridyl)-2-hydroxytetrahydrofuran (lactol) as well as methanediazohydroxide, a compound that is capable of methylating DNA. Lactol is then further oxidized to 4-hydroxy-4-(3pyridyl)butanoic acid. (Upadhyaya et al 2000).

 

How do NNK and NNAL cause cancer? -- Metabolism of NNK and NNAL are remarkably similar (See Figures above). The main metabolic activation pathway of NNK and NNAL occurs via a-hydroxylation, a reaction catalyzed by cytochrome P450 2A6 enzymes. The metabolites of NNK and NNAL result in the formation of 2 types of DNA adducts: methyl adducts such as 6/7-Methyl-guanine, or pyridloxobutyl adducts. If left unchecked these adducts result in genetic mutations that can cause cancerous tumors. In 24-50% of human primary adenocarcinomas, mutations are found on codon 12 of the KRAS gene. These mutations rarely occur in other types of tumors, and are found most often in smokers and ex-smokers. Thus, a direct correlation between mutations of codon 12 and carcinogenesis is suggested. The p16 tumor suppressor gene is inactive in approximately 70% of human lung cancers, as a result of hypermethylation on the promoter region. In one of Hecht's studies, 94% of adenocarcinomas induced by NNK in rats were found to be hypermethylated at p16. As a result, and abnormal p16 gene can be used as an indicative marker for the likely development of lung cancer (Hecht 1999). NNK has also been shown to cause pancreatic tumors in rats, making it the only pancreatic carcinogen known to be present in tobacco products (Upadhyaya et al 2000).

 

Stereospecificity and Carcinogenicity of NNK Metabolites -- NNAL contains a chiral center at the carbinol carbon (See NNAL Figure above). In its formation from NNK, two possible enantiomers can be formed: (R)-NNAL and (S)-NNAL. Considerable stereoselectivity in this metabolic pathway exists, and (S)-NNAL is the most abundant enantiomer formed during metabolic reduction of NNK in rodent liver, lung tissue, and red blood cells, as well as in human liver and red blood cells. This occurs because the rate of a-hydroxylation of the S enantiomer is much greater than that of (R)-NNAL. Unfortunately, the (S)-NNAL enantiomer as the most abundant and is also the more tumorigenic enantiomer (Upadhyaya et al 2000).

 

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