The metabolism of nicotine into two optically-active stereoisomers of nicotine-1′-oxide by animal tissues in vitro and by cigarette smokers

doi:10.1016/0006-2952(70)90236-4

Biochemical Pharmacology

Volume 19, Issue 3, March 1970, Pages 733-742

https://doi.org/10.1016/0006-2952(70)90236-4 Get rights and content

Abstract

Nicotine-1′-oxide, prepared by the oxidation of (−)-nicotine with hydrogen peroxide, has been resolved into two optically active stereoisomers by fractional precipitation with ammonium reineckate. (−)-Nicotine is enzymically oxidized into both isomers of nicotine-1′-oxide in vitro. These enzyme systems are stereospecific since guinea-pig and rabbit liver form similar amounts of each stereoisomer white BALB/c mouse and hamster liver and guinea-pig lung synthesize chiefly laevo-rotatory nicotine-1′-oxide. Both stereoisomers of nicotine-1′-oxide were identified in the urine of cigarette smokers.

References (34)

N.M. Papadopoulos
Archs Biochem. Biophys.
(1964)
R.E. McMahon et al.
Life Sci.
(1966)
M.H. Bickel et al.
Biochem. Pharmac.
(1966)
D.M. Ziegler et al.
Biochem. biophys. Res. Commun.
(1964)
J.C. Drach et al.
Biochem. Pharmac.
(1968)
A.K. Cho et al.
Biochemical and Neurophysiological Correlation of Centrally Acting Drugs
C. McMartin
Biochem. Pharmac.
(1969)
U. Breyer
Biochem. Pharmac.
(1969)
E.R. Bowman et al.
J. Pharmac. exp. Ther.
(1959)
H. McKennis

N.M. Papadopoulos

Can. J. Biochem.

(1964)

H.B. Hucker et al.

J. Pharmac. exp. Ther.

(1960)

H. McKennis et al.

J. Am. Chem. Soc.

(1959)

A. Pinner et al.

Ber. dtsch. chem. Ges.

(1891)

I. Smith

W. Bartley

Biochem. J.

(1954)

L. Kum-Tatt

J. Pharm. Pharmac.

(1960)

Cited by (51)

Nicotine, but not cotinine, has a direct toxic effect on ovarian function in the immature gonadotropin-stimulated rat
1994, Reproductive Toxicology
PMSG-primed and hCG-triggered rat ovaries were exposed to nicotine and its major metabolite, cotinine, using in vitro and in vivo experimental approaches. In vivo, a dose-dependent reduction in oocytes within the fallopian tube was noted in nicotine treated rats (6.25 ng/g animal weight, P < 0.001). Serum estradiol concentrations were also reduced in rats receiving nicotine (P < 0.04). There were no significant differences in weight gain. Cotinine had no effects. In vitro, nicotine also caused a dose-dependent reduction in oocytes in the collection chamber (P < 0.0001). Estradiol levels in nicotine-treated perfusions were reduced and reached statistical significance at 7 h (P < 0.003). The in vitro fertilization rate was reduced for nicotine-treated perfusions exposed to 1.43 pg/mL of nicotine (P < 0.001). Cotinine had no effect in vitro. We conclude that nicotine inhibits ovulation, estradiol production, and fertilization both in vivo and in vitro in rat models of ovulation. Cotinine did not affect these parameters. These effects of nicotine are notably independent of nicotine's known effect on the midcycle gonadotropin surge.
A physiologically based pharmacokinetic model for nicotine disposition in the Sprague-Dawley rat
1992, Toxicology and Applied Pharmacology
A physiologically based pharmacokinetic (PBPK) model was developed to describe the disposition of nicotine in the Sprague-Dawley (SD) rat. Parameters for the model were either obtained from the literature (blood flows, organ volumes) or determined experimentally (partition coefficients). Nicotine metabolism was defined in the liver compartment by the first-order rate constants K_NC and K_NP which control the rate of nicotine metabolism to cotinine and “polar metabolites” (PM), respectively. These rate constants were estimated by optimizing the model fit to pharmacokinetic data obtained by administering an intraarterial (S)-[5-³H] nicotine bolus of 0.1 mg/kg to 6 rats. Model simulations that optimized for the appearance of cotinine in plasma estimated K_NC and K_NP to be 75.8 and 24.3 hr⁻¹, respectively. Use of these constants in the model allowed us to accurately predict nicotine plasma kinetics and the fraction of the dose eliminated by renal (8.5%) and metabolic (91.5%) clearance. To validate the model's ability to predict tissue kinetics of nicotine, 21 male SD rats were administered 0.1 mg/kg (S)-[5-³H] nicotine intraarterially. At seven time points following treatment, 3 rats were euthanized and tissues were removed and analyzed for nicotine. Model-predicted nicotine tissue kinetics were in agreement with those determined experimentally in muscle, liver, skin, fat, and kidney. The brain, heart, and lung exhibited nonlinear nicotine elimination, suggesting that saturable nicotinic binding sites may be important in nicotine disposition in these organs. Inclusion of saturable receptor binding expressions in the mathematical description of these compartments resulted in better agreement with the experimental data. The B_max and K_D estimated by model simulation for these tissues were brain, 0.009 and 0.12; lung, 0.039 and 2.0; and heart, 0.039 nmol/tissue and 0.12 nm, respectively. This PBPK model can succesfully describe the tissue and plasma kinetics of nicotine in the SD rat and will be a useful tool for pharmacologic studies in humans and experimental animals that require insight into the plasma or tissue concentration-effect relationship.
Formation of two major nicotine metabolites in livers of guinea pigs
1987, Biochemical Pharmacology
Using antibody against NADPH-cytochrome P-450 reductase and several effectors of cytochrome P-450 and FAD-containing monooxygenase, we investigated nicotine metabolites formed by these two enzymes. When [³H]nicotine was metabolized by the combination of liver microsomes of guinea pigs and partially purified aldehyde oxidase, three distinct spots corresponding to nicotine, cotinine and nicotine-1'-oxide were observed on fluorograms of thin-layer chromatography. Antibody against NADPH-cytochrome P-450 reductase inhibited the formation of cotinine but not nicotine-1'-oxide. Metyrapone and n-octylamine inhibited the cotinine formation, while methimazole prevented the formation of nicotine-1'-oxide. These results show that microsomal electron transport systems participate in the formation of nicotine-1'-oxide and strongly suggest the involvement of FAD-containing monooxygenase in the formation of nicotine-1'-oxide.
Participation of microsomal electron transport systems in nicotine metabolism by livers of guinea pigs
1986, Biochemical Pharmacology
Pharmacokinetics of nicotine in rats after multiple-cigarette smoke exposure
1983, Toxicology and Applied Pharmacology
The pharmacokinetics of nicotine and its major metabolites was evaluated in male rats after multiple-cigarette smoke exposure. A smoke-exposure apparatus was used to deliver cigarette smoke to the exposure chamber. The rats were exposed to smoke from a single cigarette every 8 hr for 14 days and to the smoke of a cigarette spiked with radiolabeled nicotine on the 15th day. Blood and urine samples were collected at timed intervals during the 10-min smoke-exposure period of the last cigarette and up to 48 hr thereafter. Nicotine, cotinine, and other polar metabolites were separated by thin-layer chromatography and quantified by liquid scintillation counting. The data were analyzed by computer fitting, and the derived pharmacokinetic parameters were compared to those observed after a single iv injection of nicotine and after a single-cigarette smoke exposure. The results indicated that the amount of nicotine absorbed from multiple-cigarette smoke was approximately 10-fold greater than that absorbed from a single cigarette. Also, unlike the single-cigarette smoke exposure experiment, nicotine plasma levels did not decay monotonically but increased after the 5th hr, and high plasma concentrations persisted for 30 hr. The rate and extent of the formation of cotinine, the major metabolite of nicotine, were decreased as compared with their values following a single-cigarette smoke exposure. It was concluded that nicotine or a constituent of tobacco smoke inhibits the formation of cotinine and may affect the biotransformation of other metabolites. Urinary excretion tended to support the conclusions that the pharmacokinetic parameters of nicotine and its metabolites were altered upon multiple as compared to single dose exposure.
Nicotine, resorption and fate
1982, Pharmacology and Therapeutics

View all citing articles on Scopus

View full text

The metabolism of nicotine into two optically-active stereoisomers of nicotine-1′-oxide by animal tissues in vitro and by cigarette smokers

Abstract

Archs Biochem. Biophys.

Life Sci.

Biochem. Pharmac.

Biochem. biophys. Res. Commun.

Biochem. Pharmac.

Biochem. Pharmac.

Biochem. Pharmac.

J. Pharmac. exp. Ther.

Can. J. Biochem.

J. Pharmac. exp. Ther.

J. Am. Chem. Soc.

Ber. dtsch. chem. Ges.

Biochem. J.

J. Pharm. Pharmac.