C.Steven Godin

Remarkable substrate-inhibitor properties of nicotine enantiomers towards a guinea pig lung aromatic azaheterocycle N-methyltransferase

The kinetics of nicotine methylation by guinea pig lung homogenates has been investigated. An interesting stereospecificity has been observed for nicotine enantiomers. R-(+)-Nicotine is a substrate Km = 1.42 X 10(-5)M for an SAM-dependent guinea pig lung aromatic azaheterocycle N-methyltransferase, whereas S-(-)-nicotine acts as a competitive inhibitor (Ki = 6.25 X 10(-5)M) of the N-methylation of its antipode.

N-Methylation of nicotine enantiomers by human liver cytosol

Abstract— Incubation of human liver cytosol with either R‐(+)‐[3H‐N′CH3]nicotine or S‐(−)‐[3H‐N′CH3]nicotine results in the formation of the corresponding N‐methyl quaternary ammonium metabolite. A substrate stereoselectivity was observed in that the turnover number for the methylation of the S‐(−)‐isomer was 0.25 pmol mg 1 protein h−1, whereas that for the R‐(+)‐isomer was 2.11. The latter substrate exhibited an apparent Km value of 20.1 μM. Nicotine N‐methylation appears to be species‐dependent, since rat liver homogenates contained no ‘nicotine N‐methyl‐transferase’ activity, whereas with guinea‐pig liver homogenates, a substrate specificity for only R‐(+)‐nicotine was observed.

In vivo depletion of S-adenosyl-l-homocysteine and S-adenosyl-l-methionine in guinea pig lung after chronic S-(−)-nicotine administration

Guinea pig lung tissue is dramatically depleted of S-adenosyl-L-homocysteine (SAH) after chronic exposure (600 micrograms/h s.c. for 21 days) of animals to either R-(+)- or S-(-)-nicotine enantiomers; S-(-)-nicotine decreased lung SAH levels by 60-fold, while R-(+)-nicotine caused an 11-fold reduction of SAH, relative to control values. Lung S-adenosyl-L-methionine (SAM) levels were also reduced (15-fold and 9-fold reductions with R-(+)- and S-(-)-isomers, respectively) in nicotine-treated animals, compared to controls. These depletions are more pronounced with the S-(-)-enantiomer. Liver tissue levels of SAH and SAM are less affected, in fact, a 4-fold increase in liver SAH levels was observed after exposure of animals to R-(+)-nicotine. These results indicate that chronic exposure to nicotine may perturb important endogenous methyltransferase reactions, which could be a contributory factor in the toxicological effects produced by cigarette smoking.

Effect ofpropylene glycol 1,2-dinitrate on cerebral blood flow in rats: a potential biomarker for vascular headache?

Two measurable indices of toxicity that can be correlated with exposure to propylene glycol dinitrate (PGDN) were evaluated along with its metabolism. Propylene glycol dinitrate was administered by rapid i.v. injection to male Fischer-344 rats. These rats demonstrated a dose-response of blood pressure (BP) to doses of PGDN ranging from 0.1 to 30 mg/kg; the maximum fall in systolic BP occurred within 1 min of dosing. The i.v. administration of PGDN to separate groups of animals resulted in an increase in cerebral blood flow that was correlated with the dose, but a clear dose-response was not obtained.

Effect of continuous administration of nicotine on urinary histamine and Nτ-methylhistamme levels in the guinea pig

The effect of continuous subcutaneous administration of S-(-)- and R-(+)-nicotines on urinary excretion levels of histamine and N tau-methylhistamine in guinea pigs, over a 23-day period, has been studied. Urinary levels of these endogenous compounds were measured utilizing paired-ion reversed-phase high performance liquid chromatography with flow-through electrochemical detection. Urinary histamine levels of animals that had been administered either of these nicotine isomers were not significantly different from control values. Initial levels of urinary N tau-methylhistamine (days 2-3) in R-(+)- and S-(-)-nicotine-treated animals were, 2-fold and 8-fold higher, respectively than control levels but in both cases these levels returned to control values over the remainder of the time course examined (days 6-23). These results suggest that exposure to S-(-)-nicotine results in initial histamine release and/or inhibition of histamine uptake. However, longer term exposure to S-(-)-nicotine may not result in significantly altered levels of circulating histamine.

Perturbation of S-Adenosylhomocysteine and S-adenosylmethionine Levels, Inhibition of Histamine Metabolism in the Guinea Pig, by Nicotine

Previous work from our laboratory has shown that both (R-(+)-and S-(-)-nicotine enantiomers are capable of interacting with endogenous N-methyltransferase systems both in vitro and in vivo. This present study was designed to determine whether nicotine was capable of perturbing SAH and SAM levels in vivo, in guinea pig lung and liver.

In Vitro and In Vivo Biomethylation of Nicotine Enantiomers

Both S-(-)-nicotine and R-(+)-nicotine are reported to be constituents of tobacco smoke condensate. Although numerous studies have been published on the metabolic fate of the S-(-)-enantiomer, little is known about the biotransformation of the unnatural R-(+)-isomer. In this study, the comparative metabolic fates of both optical isomers of nicotine are examined.