Pharmacokinetics of Inhaled [14C]Methanol and Methanol-Derived [14C]Formate in Normal and Folate-Deficient Cynomolgus Monkeys

Dorman, David C.; Moss, Owen R.; Farris, Georgia M.; Janszen, Derek B.; Bond, James A.; Medinsky, Michele A.

doi:10.1006/taap.1994.1202

Cited by 39 publications

(35 citation statements)

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“…100 mL plasma was deproteinized with equal volume of acetonitrile and centrifuged for 7 min at 4 °C [47]. The supernatant (20 mL) was analyzed for blood methanol and formate using an HPLC refractive index detector system (Diagram-5) (Shimadzu RID, Japan) (equipped with Rezex ROA-organic acid column 300 × 7.5 mm 2 I.D., Phenomenex) with the security guard cartridge (AJO 4490 Phenomenex).…”

Section: Chemicalsmentioning

confidence: 99%

Biochemical responses and mitochondrial mediated activation of apoptosis on long-term effect of aspartame in rat brain

Iyaswamy

Sheeladevi

2014

Redox Biology

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Aspartame, an artificial sweetener, is very widely used in many foods and beverages. But there are controversies about its metabolite which is marked for its toxicity. Hence it is believed to be unsafe for human use. Previous studies have reported on methanol exposure with involvements of free radicals on excitotoxicity of neuronal apoptosis. Hence, this present study is proposed to investigate whether or not chronic aspartame (FDA approved Daily Acceptable Intake (ADI),40 mg/kg bwt) administration could release methanol, and whether or not it can induce changes in brain oxidative stress status and gene and protein expression of anti-apoptotic Bcl-2 and pro-apoptotic Bax and caspase-3 in the rat brain region. To mimic the human methanol metabolism, Methotrexate (MTX)-treated Wistar strain male albino rats were used and after the oral administration of aspartame, the effects were studied along with controls and MTX-treated controls. Aspartame exposure resulted with a significant increase in the enzymatic activity in protein carbonyl, lipid peroxidation levels, superoxide dismutase, glutathione-S-transferase, glutathione peroxidase and catalase activity in (aspartame MTX)-treated animals and with a significant decrease in reduced glutathione, glutathione reductase and protein thiol, pointing out the generation of free radicals. The gene and protein expression of pro apoptotic marker Bax showed a marked increase whereas the anti-apoptotic marker Bcl-2 decreased markedly indicating the aspartame is harmful at cellular level. It is clear that long term aspartame exposure could alter the brain antioxidant status, and can induce apoptotic changes in brain.

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Section: Chemicalsmentioning

confidence: 99%

Biochemical responses and mitochondrial mediated activation of apoptosis on long-term effect of aspartame in rat brain

Iyaswamy

Sheeladevi

2014

Redox Biology

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“…However, a complete quantitative agreement is not reach in all cases, and the TK model appears to overestimate the eect at high exposures. Although other mechanisms cannot be ruled out, such as a saturation of the folate pathway (Dorman et al 1994) or an altered kinetics of FA in the body by chloride/FA recycling (Karniski and Aronson 1985;Liesivuori and Savolainen 1987), it is indeed believed that the nonlinear kidney reabsorption constitutes a fair explanation of the results observed. A complete agreement could possibly be reached by adjustment of the nonlinear constants for renal reabsorption (V max4 , K m4 ).…”

Section: Discussionmentioning

confidence: 96%

Toxicokinetic modelling of methyl formate exposure and implications for biological monitoring

Nihlén

Droz

2000

International Archives of Occupational and Environmental Health

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A toxicokinetic (TK) model was developed to describe the inhalation exposure in humans to methyl formate (MF), a catalyst used in foundries, and to discuss biological monitoring. The TK model consisted of four compartments: MF, the metabolites--methanol (MeOH) and formic acid (FA)--and, in addition, a urinary compartment describing the saturable reabsorption of FA. Levels of MeOH and FA in urine, from an experimental study (100 ppm MF, 8 h at rest), validated the present model. The TK model describes well the general behaviour of MeOH and FA in urine after MF exposure. A nonlinear and a linear relationship respectively, was predicted between MF exposure and FA or MeOH excretion in urine, and this has previously been seen after occupational MF exposure. The present model has been modified to simulate MeOH exposure as well. Generally low exposures (concentration or exercise) produce only marginal increases in FA urinary excretions, but when exposure is elevated, urinary FA excretion increases because of saturation in the mechanism of reabsorption. Using FA urinary excretion as the critical indicator, because of its link to health effects, an occupational exposure limit value for MF of no greater than 50 ppm should be selected (based on predictions with the TK model). MeOH in urine can be considered as a biomarker for MF at low exposure, because of lower background values and of a linear relationship with exposure. At higher exposures, however, FA could be used as a biomarker as it becomes progressively more sensitive. But the use of biological monitoring for MF is difficult because of individual variations in background values. Under the present state of knowledge both FA and MeOH should be used to estimate only group exposures, rather than individual exposures.

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“…Thus, significantly higher formate levels are achieved when the folatedeficient animals are exposed to MeOH (McMartin et al 1975;Noker et al 1980;Dorman et al 1994;Lee et al 1994). Tephly has suggested that people with inadequate folate metabolism would be prone to the MeOH toxicity, because they would have difficulty metabolizing one-carbon units (Tephly 1991).…”

Section: Formate Metabolismmentioning

confidence: 99%

FASD: folic acid and formic acid — an unholy alliance in the alcohol abusing mother

Kapur

Baber

2018

Biochem. Cell Biol.

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Alcohol consumption during pregnancy remains a significant cause of preventable birth defects and developmental disabilities; however, the mechanism of toxicity remains unclear. Methanol is present as a congener in many alcoholic beverages and is formed endogenously. Because ethanol is preferentially metabolized over methanol, it has been found in the sera and cerebro-spinal fluid of alcoholics. Toxicity resulting from methanol has been attributed to formic acid. Formic acid is present in significantly higher quantities in the biofluids of alcoholics. These higher levels can be cytotoxic and cause neuronal cell death. However, the adverse effects can be mitigated by adequate levels of hepatic folic acid, because formic acid elimination depends on folic acid. During pregnancy, folate concentrations are at least 2-fold higher in cord blood then in maternal blood, owing to increased folate requirements. The reverse has been demonstrated in pregnancies with alcohol abuse, suggesting downregulation of folate transporters and low fetal folate levels. Moreover, formic acid can cross the placenta and its adverse effects can be mitigated by folic acid. Thus, the combination of low fetal folate levels and presence of formic acid form a potent cytotoxic combination that may play a significant role in the etiology of fetal alcohol spectrum disorder.Key words: formic acid, methanol, folic acid, FASD, neurotoxicity.Résumé : La consommation d'alcool pendant la grossesse demeure une cause significative de déficiences congénitales et développementales évitables, mais le mécanisme responsable de sa toxicité est encore flou. Le méthanol est présent comme congénère dans plusieurs boissons alcooliques et il est formé de manière endogène. Puisque l'éthanol est préférentiellement métabolisé par rapport au méthanol, ce dernier a été trouvé dans le sérum et le liquide céphalorachidien des personnes alcooliques. La toxicité résultant du méthanol a été attribuée à l'acide formique. L'acide formique est présent en quantité significativement plus élevée dans les liquides biologiques des patients alcooliques. Ces niveaux plus élevés peuvent être cytotoxiques et causer la mort neuronale. Cependant, ces effets nocifs peuvent être atténués par des niveaux appropriés d'acide folique hépatique, car l'élimination d'acide formique dépend de l'acide folique. Durant la grossesse, les concentrations de folate sont au moins deux fois plus élevées dans le cordon ombilical que dans le sang maternel à cause des besoins accrus en folate. L'inverse a été démontré chez les femmes enceintes qui abusent d'alcool, suggérant une régulation à la baisse des transporteurs du folate et de faibles niveaux foetaux de folate. En outre, l'acide formique peut traverser le placenta et ses effets nocifs peuvent être atténués par l'acide folique. Ainsi, de faibles niveaux foetaux de folate et la présence d'acide formique forment une combinaison cytotoxique puissante qui peut jouer un rôle significatif dans l'étiologie de troubles du spectre de l'alcoolisation foet...

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Pharmacokinetics of Inhaled [14C]Methanol and Methanol-Derived [14C]Formate in Normal and Folate-Deficient Cynomolgus Monkeys

Cited by 39 publications

References 0 publications

Biochemical responses and mitochondrial mediated activation of apoptosis on long-term effect of aspartame in rat brain

Biochemical responses and mitochondrial mediated activation of apoptosis on long-term effect of aspartame in rat brain

Toxicokinetic modelling of methyl formate exposure and implications for biological monitoring

FASD: folic acid and formic acid — an unholy alliance in the alcohol abusing mother

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