The chemical conversion of nicotinic acid and nicotinamide to derivatives of <i>N</i>-methyl-2-pyridone by methylation and oxidation

Holman, W. I. M.; Wiegand, Chr.

doi:10.1042/bj0430423

Cited by 54 publications

(12 citation statements)

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“…Olanzapine was obtained from Beijing Nordhuns Chemical Technology (Beijing, China). N 1 -ethylnicotinamide and 2-Py were synthesized according to the methods described respectively by Hirayama et al [16] and Holman et al [17] .…”

Section: Chemicalsmentioning

confidence: 99%

Nicotinamide overload may play a role in the developmentof type 2 diabetes

Zhou

Li²,

Sun³

et al. 2009

WJG

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AIM:To investigate whether nicotinamide overload plays a role in type 2 diabetes. METHODS:Nicotinamide metabolic patterns of 14 diabetic and 14 non-diabetic subjects were compared using HPLC. Cumulative effects of nicotinamide and N 1 -methylnicotinamide on glucose metabolism, plasma H2O2 levels and tissue nicotinamide adenine dinucleotide (NAD) contents of adult Sprague-Dawley rats were observed. The role of human sweat glands and rat skin in nicotinamide metabolism was investigated using sauna and burn injury, respectively. RESULTS:Diabetic subjects had significantly higher plasma N 1 -methylnicotinamide levels 5 h after a 100-mg nicotinamide load than the non-diabetic subjects (0.89 ± 0.13 μmol/L vs 0.6 ± 0.13 μmol/L, P < 0.001). Cumulative doses of nicotinamide (2 g/kg) significantly increased rat plasma N 1 -methylnicotinamide concentrations associated with severe insulin resistance, which was mimicked by N 1 -methylnicotinamide. Moreover, cumulative exposure to N 1 -methylnicotinamide (2 g/kg) markedly reduced rat muscle and liver NAD contents and erythrocyte NAD/ NADH ratio, and increased plasma H2O2 levels. Decrease in NAD/NADH ratio and increase in H2O2 generation were also observed in human erythrocytes after exposure to N 1 -methylnicotinamide in vitro . Sweating eliminated excessive nicotinamide (5.3-fold increase in sweat nicotinamide concentration 1 h after a 100-mg nicotinamide load). Skin damage or aldehyde oxidase inhibition with tamoxifen or olanzapine, both being notorious for impairing glucose tolerance, delayed N 1 -methylnicotinamide clearance. CONCLUSION:These findings suggest that nicotinamide overload, which induced an increase in plasma N 1 -methylnicotinamide, associated with oxidative stress and insulin resistance, plays a role in type 2 diabetes.

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Section: Chemicalsmentioning

confidence: 99%

Nicotinamide overload may play a role in the developmentof type 2 diabetes

Zhou

Li²,

Sun³

et al. 2009

WJG

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“…2-Pyr was prepared under the supervision of Professor T. Gallagher in the Department of Chemistry, University of Bristol, using the method of Holman and Wiegand (1948). The melting point (uncorrected) was consistent with that reported in the literature, and gave a single peak by HPLC, with the structure confirmed by NMR.…”

Section: Methodsmentioning

confidence: 78%

Measurement ofN-methyl-2-pyridone-5-carboxamide in urine by high performance liquid chromatography

Moore

Bolton

Downs

et al. 2000

Biomed. Chromatogr.

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“…After standing at Table 1. room temperature for 60 min the absorbance of the product was measured at 590 nm. Authentic methyl pyridone carboxamide for use as a standard was synthesized by the method of Holman & Wiegand (1948).…”

Section: Methodsmentioning

confidence: 99%

Effects of oestradiol and vitamin B₆on tryptophan metabolism in the rat: implications for the interpretation of the tryptophan load test for vitamin B₆nutritional status

Bender

1983

Br J Nutr

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1. The effects of the administration of oestradiol and vitamin B, on tryptophan metabolism in the rat have been assessed by measurement of the release of 14C0, from [14C]tryptophan, in vivo, in order to determine whether, and to what extent, the abnormalities of tryptophan metabolism that are associated with oestrogen administration can be attributed to drug-induced vitamin B, deficiency or depletion. Two positional isomers of [14qtryptophan have been used; tryptophan as an index of the activity of tryptophan oxygenase (L-tryptophan: oxygen oxidoreductase (decyclizing), EC 1 . 13.11 . 11) and [me~hylene-'~C]trytophan as an index of the activity of kynureninase (L-kynurenine hydrolase, EC 3.7.1 .3).2. The administration of 500 pg oestradiol/kg body-weight led to a reduction in the release of 14C0, from both positional isomers of tryptophan, suggesting that the activities of both tryptophan oxygenase and kynureninase are reduced following oestrogen treatment. The kinetics of the release of 14C0, from [methylene-14C]tryptophan after the administration of oestradiol were compatible with competitive inhibition of kynureninase by oestradiol or a metabolite.3. The administration of 10 mg pyridoxine hydrochloride/kg body-weight also reduced the production of l4COZ from both positional isomers of [14C]tryptophan, suggesting some toxicity of such a high dose of the vitamin. 4.In animals which had received the supplementary dose of vitamin B,, the administration of oestradiol led to further reduction in the production of 14C0, from [ring-2-14C]tryptophan, suggesting a further reduction in the activity of tryptophan oxygenase, and an increase in the production of 14C0, from [methylene-I4C]tryptophan, but with a delay in the peak of production.5. These results confirm that there is no induction of tryptophan oxygenase by oestradiol, but rather reduced activity of the enzyme after the administration of a relatively high dose of the hormone. They also confirm that the inhibition of kynureninase by oestrogen metabolites that has been reported previously in partially-purified enzyme preparations also occurs in vivo. 6. It is suggested that the abnormal results of the tryptophan load test that have been reported in women receiving oestrogens, and which have been interpreted as indicating some extent of drug-induced vitamin B, deficiency, can be accounted for by the inhibition of tryptophan metabolism by oestrogens or their metabolites.Therefore it seems likely that the practice of administering supplements of vitamin B, to women receiving oestrogens may not be appropriate, and indeed may exacerbate the changes in tryptophan metabolism that result from the administration of oestrogens. The tryptophan load test would appear to be unreliable as an index of vitamin B, nutritional status in women receiving oestrogens.The tryptophan load test for vitamin B, nutritional status depends on the fact that kynureninase (L-kynurenine hydrolase, EC 3 . 7 . 1 .3) is a pyridoxal phosphate-dependent enzyme and, in vitamin B, deficiency, the activ...

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The chemical conversion of nicotinic acid and nicotinamide to derivatives of N-methyl-2-pyridone by methylation and oxidation

Cited by 54 publications

References 2 publications

Nicotinamide overload may play a role in the developmentof type 2 diabetes

Nicotinamide overload may play a role in the developmentof type 2 diabetes

Measurement ofN-methyl-2-pyridone-5-carboxamide in urine by high performance liquid chromatography

Effects of oestradiol and vitamin B₆on tryptophan metabolism in the rat: implications for the interpretation of the tryptophan load test for vitamin B₆nutritional status

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The chemical conversion of nicotinic acid and nicotinamide to derivatives of N-methyl-2-pyridone by methylation and oxidation

Cited by 54 publications

References 2 publications

Nicotinamide overload may play a role in the developmentof type 2 diabetes

Nicotinamide overload may play a role in the developmentof type 2 diabetes

Measurement ofN-methyl-2-pyridone-5-carboxamide in urine by high performance liquid chromatography

Effects of oestradiol and vitamin B6on tryptophan metabolism in the rat: implications for the interpretation of the tryptophan load test for vitamin B6nutritional status

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Effects of oestradiol and vitamin B₆on tryptophan metabolism in the rat: implications for the interpretation of the tryptophan load test for vitamin B₆nutritional status