A previously undescribed chemical link between smoking and metabolic disease - PubMed (original) (raw)

Tobin J Dickerson et al. Proc Natl Acad Sci U S A. 2002.

Abstract

Over the past 20 years, protein glycation has been implicated in a variety of pathological states. Although smoking also can contribute to many of these diseases, the precise mechanism by which this occurs is not known. Previously, we have demonstrated that nornicotine, a constituent of tobacco and metabolite of nicotine, can catalyze aldol reactions under aqueous conditions. This finding has caused us to question whether this reaction has physiological consequences. We now report that nornicotine causes aberrant protein glycation and catalyzes the covalent modification of certain prescription drugs such as the commonly used steroid, prednisone. Furthermore, we show that the plasma of smokers as compared with nonsmokers contains higher concentrations of nornicotine-modified proteins, suggesting an unrecognized pathway for the development of the pathology of tobacco abuse.

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Figures

Fig 1.

Fig 1.

(a) Amadori product derived from the reaction of glucose and a primary amine. (b) Formation of nornicotine-based Amadori product 2 from glucose and nornicotine 1. This intermediate can undergo further chemical reaction including oxidation to a 1,2-dicarbonyl-containing compound, a critical intermediate found in protein glycation.

Fig 2.

Fig 2.

Covalent catalysis of the aldol reaction by nornicotine via an enamine intermediate.

Fig 3.

Fig 3.

Hapten 3 used to elicit anti-nicotine mAbs.

Fig 4.

Fig 4.

Chemical modification of proteins with nornicotine. SDS/PAGE and Western blot with mAb NIC6C12 of samples are shown. (a) BSA (lane 1), BSA + nornicotine and glucose (lane 2), HSA (lane 3), HSA + nornicotine and glucose (lane 4). (b) Chemoluminescent development of Western blot from human plasma; HSA + nornicotine and glucose (lane 1), nonsmoker sample A total protein concentrations of 2.5 mg/ml (lane 2), 5.0 mg/ml (lane 3), 10 mg/ml (lane 4); nonsmoker sample B total protein concentrations of 2.5 mg/ml (lane 5), 5.0 mg/ml (lane 6), 10 mg/ml (lane 7); smoker sample C total protein concentrations of 2.5 mg/ml (lane 8), 5.0 mg/ml (lane 9), 10 mg/ml (lane 10); smoker sample D total protein concentrations of 2.5 mg/ml (lane 11), 5.0 mg/ml (lane 12), 10 mg/ml (lane 13). Reactions were performed by incubating sterile solutions (0.2-μm filter) of glucose (200 mM), nornicotine (0.8 mM), and protein (0.8 mM) in phosphate buffer (200 mM, pH 7.4) in the dark at 37°C.

Fig 5.

Fig 5.

Two products formed on reaction of nornicotine with prednisone, the prednisone Heyns rearrangement product, and 22-hydroxy-prednisone.

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