Detoxification Pathways for NNK and NNAL:

Defenses Against Cancer

 

 

The grim facts about nicotine and its effects on human health presented here may leave one wondering: "Is there any hope?" Humans encounter countless carcinogenic substances and other environmental hazards on a daily basis, and fortunately the body has numerous methods of dealing with these compounds that are relatively efficient. The compounds present in cigarettes and other tobacco products indeed pose a threat to the health of those that consume them, but the defense mechanisms against these carcinogens are presented here:

Glucuronidation -- The body has several methods by which NNK and NNAL are detoxified and excreted. Primary detoxification mechanisms are usually governed by enzymes such as cytochrome P450, but glucuronidation is the main secondary pathway for NNAL detoxification. The product of this detoxification reaction is [4-(methylnitrosamino)-1-(3-pyridyl)-but-1-yl]b-O-D- Glucuronidation is the main pathway for NNAL detoxification, yielding [4-(methylnitrosamino)-1-(3-pyridyl)-but-1-yl]b-O-D-glucosiduronic acid, or NNAL-Gluc (see Figure at right). In the process of glucuronidation, UDP-glucuronic acid (UDPglucUA) is used as a cosubstrate in a catalytic reaction using non-membrane associated substrates (like NNK and NNAL) including steroids, bile acids, hormones, dietary compounds, drugs, toxins, and carcinogens. This pathway has become quite specialized in higher organisms, utilizing UDP-glucuronosyltransferases to transfer beta-D-glucuronides to the substrate via hydroxyl, carboxyl, sulfuryl, carbonyl, or amino linkages. The wide variety of available linkages makes glucuronidation a feasible procedure for a vast number of compounds. After a substrate (in this case NNK) has been glucuronidated, a previously lipophilic substrate can be incorporated into the aqueous compartments of the body for facile transport to the excretory organs. The glucuronidation pathway is mainly a catabolic one, and thus is classified as a detoxification mechanism (Tukey & Strassburg 2000).

Pyridine-N-Oxidation -- NNAL can also by detoxified via pyridine-N-oxidation to give 4(methylnitrosamino)-1-(3pyridyl-N-oxide)-1-butanol, or NNAL-N-oxide (See Figure above). Pyridine-N-oxidation is also used to detoxify NNK to form NNK-N-oxide. The process of Pyridine-N-oxidation involves formation of a coordinate covalent bond between the nitrogen of the pyridine ring to an oxygen atom. This reaction is also catalyzed by cytochrome P450 in the liver, and serves to transform NNK adn NNAL into more readily-excreteable forms (Upadhyaya et al. 2000, Groves & Han 1995).

Detoxification and Stereospecificity -- Glucuronidation occurs more readily with the (S)-NNAL enantiomer in monkeys, and likely in humans as well. The purpose of adding a glucose ring or a coordinate N-->O bond is to further solubilize NNK and NNAL for facile excretion in the urine. Humans exposed to NNK have (S)-NNAL as the major circulating enantiomer, but (S)-NNAL-Gluc is the predominate compound found in smoker urine. Thus, even though the (S)-NNAL enantiomer of NNAL is the most carcinogenic, it is also the most easily detoxified form. The extent to which the body can diminish initial concentrations of (S)-NNAL and excrete the metabolic products of NNAL varies widely from person to person (Upadhyaya et al. 2000).

 

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