Structure of hydroxycotinine, a nicotine methobolite

Dagne, Ermias; Castagnoli, Neal

doi:10.1021/jm00274a005

Cited by 67 publications

(30 citation statements)

References 2 publications

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“…Since 3Ј-hydroxycotinine is a major metabolite of cotinine, in humans and rhesus monkeys, it is not unreasonable to propose that 3Ј-hydroxynorcotinine is a metabolite of norcotinine (Dagne and Castagnoli, 1972;Gorrod and Schepers, 1999). However, we were unable to detect 3Ј-hydroxynorcotinine as a metabolite of norcotinine in vitro with patas monkey liver microsomes (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Metabolism and Pharmacokinetics ofN′-Nitrosonornicotine in the Patas Monkey

Upadhyaya¹,

Zimmerman

Hecht³

2002

Drug Metab Dispos

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:N-Nitrosonornicotine (NNN) is present in significant quantities in tobacco and tobacco smoke and is believed to play an important role as a cause of cancer in people who use tobacco products. Biomarkers of NNN uptake in humans such as urinary metabolites would be useful for assessing cancer risk. Previous studies, carried out almost exclusively in rodents, have characterized urinary metabolites of NNN, but none of these would be suitable as a biomarkers of NNN uptake in humans. Therefore, we studied NNN metabolism in the patas monkey. Monkeys were treated intravenously with

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Section: Discussionmentioning

confidence: 99%

Metabolism and Pharmacokinetics ofN′-Nitrosonornicotine in the Patas Monkey

Upadhyaya¹,

Zimmerman

Hecht³

2002

Drug Metab Dispos

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“…Thus, cotinine has been recommended as a parameter for nicotine consumption or abstinence (e. g. Benowitz et al 1983) and it has been demonstrated that plasma concentrations of cotinine are related to nicotine intake in man (Galeazzi et al 1985). Cotinine, which is a long-lived metabolite of nicotine, may enter secondary metabolic pathways leading to cotinine-N-oxide, norcotinine and trans-3'-hydroxycotinine (Wada et al 1961;Bowman and McKennis 1962;Dagne and Castagnoli 1972;Hibbert and Gorrod 1985). The participation of cytochrome P-450 during N-oxidation of cotinine at the pyridine ring has been reported (Hibbert and Gorrod 1985), while the other enzymic pathways of cotinine transformation have not been fully elucidated yet.…”

Section: Discussionmentioning

confidence: 99%

Nicotine metabolism in isolated perfused lung and liver of phenobarbital- and benzoflavone-treated rats

et al. 1991

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The kinetics of nicotine elimination was investigated in isolated perfused lung and liver of phenobarbital (PB)- and 5,6-benzoflavone (BF)-pretreated rats. The estimated kinetic parameters demonstrated a high nicotine elimination rate in rat lung approaching the capacity of liver when both organs were in an uninduced state. The concentration-time profiles of cotinine as the main metabolite were almost identical for isolated lung and liver. In both organs the cotinine plasma concentrations reached a plateau level after 60 min of perfusion. Pretreatment of rats with 5,6-benzoflavone did not affect the rate of nicotine elimination and cotinine formation either in the lung or in the liver. Phenobarbital treatment, however, induced nicotine clearance in lung approximately 2-fold. This effect is quantitatively lower than the PB-related 8-fold induction of hepatic nicotine elimination observed in a previous study. The present results also indicate that the turnover of cotinine is markedly enhanced after PB induction. The elimination half-lives and clearance values for cotinine as the substrate were approximately 10-fold increased in rat liver after PB pretreatment. Thus, an important contribution of extrahepatic tissues to nicotine metabolism in rats has to be assumed. Moreover, since cotinine elimination is significantly increased after PB induction it is questionable whether cotinine plasma concentrations can further be used as suitable parameter for nicotine consumption.

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“…Cotinine enters secondary metabolic pathways leading to trans-3'-hydroxycotinine, norcotinine, cotinine-N-oxide, 5'-hydroxycotinine and N-methylcotininium ion [5,7,8,15,20,23]. The participation of cytochrome P-450 in N-oxidation of cotinine has been reported [17] and a recent study has demonstrated that cotinine interacts with hepatic cytochrome P-450 [4].…”

Section: Discussionmentioning

confidence: 99%

Increased cotinine elimination and cotinine-N-oxide formation by phenobarbital induction in rat and mouse

Foth¹,

Aubrecht²,

Höhne³

et al. 1992

Clin Investig

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The metabolic fate of cotinine, the major metabolite of nicotine, was studied in phenobarbital-induced and non-induced isolated perfused rat lung and liver and in isolated hepatocytes of rats and mice. The non-induced lung tissue showed low cotinine metabolizing capacity while the perfused liver was approximately four times more active. After phenobarbital pretreatment the metabolism of cotinine was increased eight-fold in the intact liver. A substantial increase in cotinine metabolism was also found in isolated hepatocytes from PB-induced rats and in cultured mouse hepatocytes grown in a medium supplemented with PB. This was paralleled by an increased formation of cotinine-N-oxide which could be inhibited by 100 microM metyrapone. In contrast, the pulmonary elimination of cotinine was not affected by PB. A dominant role of primary N-oxidation of nicotine compared to C-oxidation was apparent in non-induced rat liver. After PB treatment the rate of nicotine-N'-oxide formation dropped markedly while the cotinine related pathways were increased causing an inversion of the N- to C-oxidation ratio. In the lung, cotinine formation was the preferred metabolic pathway of nicotine already in non-induced organs. The pattern of nicotine metabolites was not altered by PB induction. In conscious PB-induced rats receiving nicotine orally or intravenously, 3'-hydroxycotinine was found as the main urinary metabolite of nicotine while only a small fraction was excreted as cotinine-N-oxide. This discrepancy between the profile of nicotine metabolites in perfused liver and lung and in the urine in vivo indicates that extrahepatic organs other than the lung may be important sites of cotinine metabolism.

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Structure of hydroxycotinine, a nicotine methobolite

Cited by 67 publications

References 2 publications

Metabolism and Pharmacokinetics ofN′-Nitrosonornicotine in the Patas Monkey

Metabolism and Pharmacokinetics ofN′-Nitrosonornicotine in the Patas Monkey

Nicotine metabolism in isolated perfused lung and liver of phenobarbital- and benzoflavone-treated rats

Increased cotinine elimination and cotinine-N-oxide formation by phenobarbital induction in rat and mouse

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