Nicotine metabolism pathways

Nicotinic acid derivatives occur in biologic materials as the free acid, as nicotinamide, and in two coenzymatic forms nicotinamide adenine dinucleotide (NAD), and nicotinamide adenine dinucleotide phosphate (NADP). These coenzymes act in series with flavoprotein enzymes and, like them, are hydrogen acceptors or, when reduced, donors. Several plants and bacteria use a metabolic pathway for the formation of nicotinic acid that is different from the tryptophan pathway used by animals and man (B39). 

Fig. 3 Pathways of nicotine metabolism. Reprinted with permission from Hukkanen et at. 2005c...

Taken with alcohol they potentiate the sedative effects and impairment of psychomotor performance. Hepatic enzyme induction by barbiturates or nicotine may reduce plasma levels. Cimetidine may increase levels by enzyme inhi bition. Some antipsychotic drugs may compete for similar metabolic pathways. 

Niacin is a generic term which refers to two related chemical compounds, nicotinic acid (6.22) and its amide, nicotinamide (6.23) both are derivatives of pyridine. Nicotinic acid is synthesized chemically and can be easily converted to the amide in which form it is found in the body. Niacin is obtained from food or can be synthesized from tryptophan (60 mg of dietary tryptophan has the same metabolic effect as 1 mg niacin). Niacin forms part of two important co-enzymes, nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP), which are co-factors for many enzymes that participate in various metabolic pathways and function in electron transport. 

This transformation is part of a microbial metabolic pathway in which nicotinate is broken down into ammonia, CO2, acetate and pyruvate [16, 68]. Accepting the bound free-radical hypothesis implies that the cmcial radical rearrangement step can be represented by reaction 4, in which a 2-methyleneglutarate-derived radical (1) is transformed into an (/ )-3-methylitaconate-related radical (2) [6] ... 

The overexpression of both trl and h6h from H. niger in N. tabacum plants have been reported [160]. Here, transgenic and control tobacco plants were fed with the tropane intermediate tropinone. Thus, tropine, the TRI-reaction product, was detected only in leaves of transgenic plants, with no correlation with trl transcript level and tropine amounts. Surprisingly, transgenic tobacco plants contained 3 to 13-fold more nicotine than wild type plants. Also, the presence of considerable amounts of nornicotine, myosmine, anabasine and anatabine contrasted with low levels in wild-type plants, indicating that the overexpression of trl and h6h perturb the normal nicotine biosynthesis when these new genes taken from a different metabolic pathway are introduced in tobacco [160]. 

The mephenytoin metabolic pathway is utilized by commonly used drugs, such as mephobarbital, hexobarbital, diazepam, imipramine and omepra-zol, but only 3-5% of Caucasians and 8% of Blacks are poor metabolizers of mephenytoin, compared to 15-20% of Chinese and Japanese populations (Kupfer et al., 1988). This enzyme s activity is inhibited by floconazole and fluoxetine and induced by drugs such as barbiturates and nicotine (smoking). 

Of note in the above study was the finding that the clearance of nicotine and the fractional conversion of nicotine to cotinine were significantly correlated (r = 0.59). This correlation suggests that cotinine is the most rapid or rate-limiting pathway for nicotine metabolism. Thus, people who metabolize nicotine via pathways other than those to cotinine are likely to have slower elimination of nicotine in general. 

Besides being fundamental constituents of proteins they are the parent substances from which powerful hormones are derived, for example, adrenaline (epinephrine), noradrenaline (norepinephrine), thyroxine and related substances, 5-hydroxytryptamine (enteramine, serotonin), and the plant hormone indoleacetic acid. Tryptophan is also the precursor of the B vitamin nicotinic acid and hence of part of the important pyridine nucleotides. All three aromatic amino acids are potential precursors of other substances having powerful physiological activity, for example, many of the alkaloids. Errors in the metabolism of the aromatic amino acids in man can give rise to sometimes serious, but fortunately comparatively rare, disorders such as alkaptonuria and phenylketonuria. The numerous metabolic pathways involved in aromatic amino acid metabolism therefore make an important as well as an interesting study. 

The metabolic pathways involved in the biotransformation of nicotine and haloperidol involve the initial formation of an aroylpropionic acid [3-nicotinoylpropionic and... 

Figure 4. Metabolic pathways of nicotine in mammals. Solid arrows show established pathways broken arrows indicate unconfirmed reactions.

C.B. Dewey Cotinine pathway of nicotine metabolism Am. Chem. Soc. Mtg. (1957). 

The major metabolic pathway of terminal acetylenic derivatives is via oxidation to the corresponding acetic acid derivatives. Thus, Sullivan and coworkers and Wade and coworkers showed in 1979 that the major metabolites of ethynylbiphenyls in the rat were biphenyl-4-yl acetic acids. These metabolites are further oxidized to 4 -hydroxybiphenyl-4-yl acetic acids before being excreted in the urine (Scheme 4). Because the in vitro metabolism of biphenylacetylenes by rat liver microsomes requires nicotine-adenine-dinucleotide phosphate (NADPH) and molecular oxygen and is inhibited by carbon monoxide, it was concluded that the oxidative metabolism of the acetylenes to the corresponding acetic acid derivatives is mediated by cytochrome P450 . Acetic acid... 

However, the distribution of the individual compounds is restricted. This was first pointed out by Sachs (1882) and Pfeffer (1897), who demonstrated the lack of phylogenetic continuity of secondary substances such as oxalate, resins, and essential oils in the plant kingdom. Usually the more chemical reactions necessary for the synthesis of a given secondary product, the more restricted is its distribution. The alkaloid, nicotine, which is formed by a relatively simple biosynthetic pathway (D 16.2) occurs in many different plant species, whereas the much more complicated alkaloid brucine (D 21.3), is synthesized by only one genus of the Loganiaceae. In other words, the probabiUty that a given metabolic pathway... 

Figure 7.3 NAD recycling. Humans have two metabolic pathways that are able to recycle nicotinamide. NAD-consuming enzymes (ARTs, PARPs, sirtuins) break down NAD to nicotinamide and ADP-ribosyl product. Nicotinamide by the enzymatic action of nicotinamide phosphoribosyltransferase (NAMP/PBEF) and nicotinamide/nicotinate-mononucleotide-adenyltransferases isoenzymes (NMATl-3) is then retransformed to NAD. In a second pathway, nicotinamide riboside is phosphorylated by nicotinamide riboside kinase (NRK 1,2) to nicotinamide mononucleotide. Subsequently, nicotinamide mononucleotide is converted to NAD by the catalytic action of NMNATs.

The ketonic acid corresponding to tryptophan is a-keto-j -indolyl-pynivic acid, which can be obtained by transamination. The metabolism of this substance is unknown but it is not the main metabolic pathway for tryptophan which follows a series of different paths, as shown in Fig. 53. The most notable of these is the one leading to nicotinic acid. 

After a longer feeding of Nicotiana rustica with uniformly labeled [ C] nicotine, Tso and Jeffrey (1961) showed that radioactivity was detectable in amino acids, pigments, organic acids, and sugars large portions of the isotope from uniformly labeled [ N] nicotine administered simultaneously were found in the amino acid fraction (both free and after hydrolysis). Although none of the labeled specific metabolites were characterized, the authors demonstrated that nicotine in the plant is in a dynamic state that is connected with the primary metabolic pathways. 

Figure 6.18a. A postulated metabolic pathway of nicotine (Kisaki and Tamaki, 1966). Courtesy of the authors and Pergamon Press, Ltd., copyright 1966.

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