Metabolism of Nicotine

Kyerematen, Gabriel A.; Vesell, Elliot S.

doi:10.3109/03602539109029754

Cited by 134 publications

(74 citation statements)

References 124 publications

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“…Therefore, the effects of cotinine infusion upon hepatic respiration, carbohydrate, and lipid metabolism were measured in perfused livers from fed rats. The concentrations of cotinine used were greater than nicotine concentrations since concentrations in vivo are reported to be 10 times greater (Kyerematen and Vesell, 1991). Oxygen uptake was significantly increased from basal levels of 118 Ϯ 5 to 137 Ϯ 2 mol/g/h after infusion of 1.25 mM cotinine (Table 3).…”

Section: Inhibition Of the Adenine Nucleotide Translocasementioning

confidence: 91%

Nicotine Increases Hepatic Oxygen Uptake in the Isolated Perfused Rat Liver by Inhibiting Glycolysis

Dewar

Bradford²,

Thurman³

2002

J Pharmacol Exp Ther

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Nicotine influences energy metabolism, yet mechanisms remain unclear. Since the liver is one of the largest organs and performs many metabolic functions, the goal of this study was to determine whether nicotine would affect respiration and other metabolic functions in the isolated perfused liver. Infusion of 85 M nicotine caused a rapid 10% increase in oxygen uptake over basal values of 105 Ϯ 5 mol/g/h in perfused livers from fed rats, and an increase of 27% was observed with 850 M nicotine. Concomitantly, rates of glycolysis of 105 Ϯ 8 mol/g/h were decreased to 52 Ϯ 9 mol/g/h with nicotine, whereas ketone body production was unaffected. Nicotine had no effect on oxygen uptake in glycogen-depleted livers from 24-h fasted rats. Furthermore, addition of glucose to perfused livers from fasted rats partially restored the stimulatory effect of nicotine. Infusion of atractyloside, potassium cyanide, or glucagon blocked the nicotine-induced increase in respiration. Intracellular calcium was increased in isolated hepatocytes by nicotine, a phenomenon prevented by incubation of cells with d-tubocurarine, a nicotinic acetylcholine receptor antagonist. Respiration was also increased ϳ30% in hepatocytes isolated from fed rats by nicotine, whereas hepatocytes isolated from fasted rats showed little response. In the presence of N- [2-(pbromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H-89), an inhibitor of cyclic AMP-dependent protein kinase A, nicotine failed to stimulate respiration. These data support the hypothesis that inhibition of glycolysis by nicotine increases oxygen uptake due to an ADP-dependent increase in mitochondrial respiration.

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Section: Inhibition Of the Adenine Nucleotide Translocasementioning

confidence: 91%

Nicotine Increases Hepatic Oxygen Uptake in the Isolated Perfused Rat Liver by Inhibiting Glycolysis

Dewar

Bradford²,

Thurman³

2002

J Pharmacol Exp Ther

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“…The short half-life of cotinine (5 . 2 h) in rats (Kyerematen & Vesell 1991) and the interval between the last exposure of mothers to smoke and the killing (2 h) explain the low cotinine levels of S pups. Thus, offspring were exposed to low nicotine levels and only through the milk, similar to what occurs with infants whose mothers smoked between the breastfeeding periods, away from their babies.…”

Section: Discussionmentioning

confidence: 99%

Effects of tobacco smoke exposure during lactation on nutritional and hormonal profiles in mothers and offspring

Santos-Silva

Oliveira²,

Pinheiro³

et al. 2011

Journal of Endocrinology

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Exposure to tobacco smoke is related to changes in energy balance regulation and several endocrine dysfunctions. Previously, we showed that maternal nicotine (the main addictive compound of tobacco) exposure exclusively during lactation affects biochemical profiles in mothers, milk, and pups. As the possible consequences for mothers and offspring of maternal smoking during lactation are still unknown, we evaluated the effects of tobacco smoke exposure on nutritional, biochemical, and hormonal parameters in dams and pups at weaning. After 72 h from birth, lactating rats were divided into two groups: smoke-exposed (S) in a cigarette-smoking machine, 4!1 h per day throughout the lactation period without pups; control (C), rats were treated the same as the experimental group but exposed to filtered air. Dams and pups were killed at weaning (21 days of lactation). Body weight and food intake were evaluated. Milk, blood, visceral fat, adrenal, and carcass were collected. S dams showed hyperprolactinemia (C50%), hypoinsulinemia (K40%), hypoleptinemia (K46%), as well as lower triglycerides (K53%) and very low-density lipoprotein cholesterol (K50%). Milk of S dams had higher lactose (C52%) and triglycerides (C78%). S pups presented higher body protein (C17%), lower total (K24%) and subcutaneous fat contents (K25%), hypoglycemia (K11%), hyperinsulinemia (C28%), hypocorticosteronemia (K40%), lower adrenal catecholamine content (K40%), hypertriglyceridemia (C34%), higher high-density lipoprotein cholesterol (C16%), and lower low-density lipoprotein cholesterol (K45%). In conclusion, tobacco smoke exposure leads to changes in nutritional, biochemical, and hormonal parameters in dams and, passively through the milk, may promote several important metabolic disorders in the progeny.

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“…34) Associations between genetic polymorphisms of the CYP2A6 gene and smoking behavior or the risk of lung cancer have also been suggested. [35][36][37] EŠects of CYP2A6 Deletion on Comprehensive Nicotine Metabolism…”

Section: Interindividual Dišerences In Cotinine Formation Andmentioning

confidence: 99%

Interindividual Variability in Nicotine Metabolism: C-Oxidation and Glucuronidation

Nakajima

Yokoi

2005

Drug Metabolism and Pharmacokinetics

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Summary: Nicotine has roles in the addiction to smoking, replacement therapy for smoking cessation, as a potential medication for several diseases such as Parkinson's disease, Alzheimer's disease, and ulcerative colitis. The absorbed nicotine is rapidly and extensively metabolized and eliminated to urine. A major pathway of nicotine metabolism is C-oxidation to cotinine, which is catalyzed by CYP2A6 in human livers. Cotinine is subsequently metabolized to trans-3?-hydroxycotinine by CYP2A6. Nicotine and cotinine are glucuronidated to N-glucuronides mainly by UGT1A4 and partly by UGT1A9. Trans-3?-hydroxycotinine is glucuronidated to O-glucuronide mainly by UGT2B7 and partly by UGT1A9. Approximately 90z of the total nicotine uptake is eliminated as these metabolites and nicotine itself. The nicotine metabolism is an important determinant of the clearance of nicotine. Recently, advances in the understanding of the interindividual variability in nicotine metabolism have been made. There are substantial data suggesting that the large interindividual diŠerences in cotinine formation are associated with genetic polymorphisms of the CYP2A6 gene. Interethnic diŠerences have also been observed in the cotinine formation and the allele frequencies of the CYP2A6 alleles. Since the genetic polymorphisms of the CYP2A6 gene have a major impact on nicotine clearance, its relationships with smoking behavior or the risk of lung cancer have been suggested. The metabolic pathways of the glucuronidation of nicotine, cotinine, and trans-3?-hydroxycotinine in humans would be one of the causal factors for the interindividual diŠerences in nicotine metabolism. This review mainly summarizes recent results from our studies.

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Metabolism of Nicotine

Cited by 134 publications

References 124 publications

Nicotine Increases Hepatic Oxygen Uptake in the Isolated Perfused Rat Liver by Inhibiting Glycolysis

Nicotine Increases Hepatic Oxygen Uptake in the Isolated Perfused Rat Liver by Inhibiting Glycolysis

Effects of tobacco smoke exposure during lactation on nutritional and hormonal profiles in mothers and offspring

Interindividual Variability in Nicotine Metabolism: C-Oxidation and Glucuronidation

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