2-Acetyl-4(5)-(1,2,3,4-tetrahydroxybutyl)imidazole: detection in commercial Caramel Color III and preparation by a model browning reaction

Kröplien, U.; ROSDORFER, J.; Greef, J. van der; Long, Robert C.; Goldstein, J. H.

doi:10.1021/jo00207a047

Cited by 55 publications

(25 citation statements)

References 3 publications

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“…This lymphopenic effect has since been the focus of extensive toxicity studies and was shown to be linked to vitamin B 6 metabolism. In 1985, THI was identified as the imidazole-derived contaminant of caramel class III food colourings triggering the observed lymphopenia [9][10][11] . Yet, until today the molecular mechanism linking THI exposure to lymphopenia has not been revealed.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of human pyridoxal kinase by 2-acetyl-4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)imidazole (THI)

Elsinghorst

Salvo

Parroni

et al. 2014

Journal of Enzyme Inhibition and Medicinal Chemistry

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2-Acetyl-4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)imidazole (THI) is observed as a minor contaminant in caramel food colourings (E 150c). Feeding experiments with rodents have revealed a significant lymphopenic effect that has been linked to the presence of THI in these food colourings. Pyridoxal kinase inhibition by THI has been suggested, but not demonstrated, as a mode of action as it leads to lowered levels of pyridoxal-5 0 -phosphate, which are known to cause lymphopenia. Recently, THI was also shown to inhibit sphingosine-1-phosphate lyase causing comparable immunosuppressive effects and derivatives of THI are being developed for the treatment of rheumatoid arthritis in humans. Interestingly, sphingosine-1-phosphate lyase activity depends on pyridoxal-5 0 -phosphate, which in turn is provided by pyridoxal kinase. This report shows that THI does inhibit pyridoxal kinase with competitive and mixed-type non-competitive behaviour towards its two substrates, pyridoxal and ATP, respectively. The corresponding inhibition constants are in the low millimolar range.

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Section: Introductionmentioning

confidence: 99%

Inhibition of human pyridoxal kinase by 2-acetyl-4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)imidazole (THI)

Elsinghorst

Salvo

Parroni

et al. 2014

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…19 The immunosuppressive effects of 3 on the immune system have been well documented. 20 Interestingly, oral administration of 3 to mice was reported 21 to result in pharmacology that was strikingly similar to the phenotype that we observed in our mouse line expressing reduced S1PL.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Sphingosine-1-Phosphate Lyase for the Treatment of Autoimmune Disorders

et al. 2009

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During nearly a decade of research dedicated to the study of sphingosine signaling pathways, we identified sphingosine-1-phosphate lyase (S1PL) as a drug target for the treatment of autoimmune disorders. S1PL catalyzes the irreversible decomposition of sphingosine-1-phosphate (S1P) by a retro-aldol fragmentation that yields hexadecanaldehyde and phosphoethanolamine. Genetic models demonstrated that mice expressing reduced S1PL activity had decreased numbers of circulating lymphocytes due to altered lymphocyte trafficking, which prevented disease development in multiple models of autoimmune disease. Mechanistic studies of lymphoid tissue following oral administration of 2-acetyl-4(5)-(1(R),2(S),3(R),4-tetrahydroxybutyl)-imidazole (THI) 3 showed a clear relationship between reduced lyase activity, elevated S1P levels, and lower levels of circulating lymphocytes. Our internal medicinal chemistry efforts discovered potent analogues of 3 bearing heterocycles as chemical equivalents of the pendant carbonyl present in the parent structure. Reduction of S1PL activity by oral administration of these analogues recapitulated the phenotype of mice with genetically reduced S1PL expression.

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“…The effect of AC is evident after 2-3 days of dosage, and after withdrawal of AC lymphocyte counts return within days to baseline levels; the effects of AC on lymphocyte subpopulations have not hitherto been ascertained. Pyridoxine deficiency of the diet was shown to augment the lymphopenia-inducing capacity of AC, and the component of AC which caused lymphopenia in rats was identified as THI (5)(6)(7)(8). In rats, the effects of THI may be transient and, at dose levels that have only marginal effects on lymphocytes, the animals may develop a tolerance (C. Chappel, pers.…”

Section: Discussionmentioning

confidence: 99%

“…Deficiency of pyridoxine (Vitamin B6) in the diet was shown to augment the lymphopeniainducing capacity of AC (4). The component of AC which causes lymphopenia in the rat is 2-acetyi-4(5)-tetrahydroxybutylimidazole (THI) (5)(6)(7)(8). The aim of the present study was to ascertain whether THI induced lymphopenia in mice as it does in rats and, if so, the doses required to induce this effect.…”

Section: Introductionmentioning

confidence: 98%

Lymphopenic effects on mice of a component of ammonia caramel, 2‐acetyl‐4(5)‐tetrahydroxybutylimidazole (THI)

1988

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Summary A derivative of ammonia caramel colour (AC) is known to induce a selective lymphopenia in rats. Accordingly, the haematological effects were studied in mice of oral administration in drinking water of 2-acetyl-4(5)-tetrahydroxybutylimidazole (THI), the component of AC responsible for lymphopenia. Initially five groups of BALB/c mice (five mice per group) were given doses of THI ranging from 0 to 200 parts/10^ and bled weekly. Doses of THI from 5 to 100 parts/10^ had no effect on circulating leucocytes over 6 weeks, but lymphopenia occurred with 200 parts/10^. An increase in the concentration of T"HI to 400 parts/10^ in the group on the lowest dose resulted in lymphopenia. An increase indosagein two groups of mice, to 1000 and 2000 parts/10^. resulted in marked lymphopenia. The number of neutrophils. eosinophils and monocytes remained unchanged throughout the experiment. Measurement of the proportions of CD4(L3T4)"'" and CD8(Ly2)"^ lymphocytes in lymph nodes from mice on high doses of THI did not show a selective depression of either subset, although both were increased relative to non-T cells. THI causes a selective lymphopenia in mice, as in rats, but at relatively higher doses, and merits investigation in mice as an experimental treatment for states of lymphocyte excess or overactivity.

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2-Acetyl-4(5)-(1,2,3,4-tetrahydroxybutyl)imidazole: detection in commercial Caramel Color III and preparation by a model browning reaction

Cited by 55 publications

References 3 publications

Inhibition of human pyridoxal kinase by 2-acetyl-4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)imidazole (THI)

Inhibition of human pyridoxal kinase by 2-acetyl-4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)imidazole (THI)

Inhibition of Sphingosine-1-Phosphate Lyase for the Treatment of Autoimmune Disorders

Lymphopenic effects on mice of a component of ammonia caramel, 2‐acetyl‐4(5)‐tetrahydroxybutylimidazole (THI)

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