ascorbic-acid and methylformamide

The toxicity of daily subcutaneously applied 500 mg/kg N-methylformamide (NMF) during a period of 8 days in female CD-mice was ameliorated when 100 mg/kg sodium ascorbate, 60 mg/kg menadione bisulfite or 80 mg/kg pyridoxal hydrochloride were applied simultaneously. The comparison of the daily s.c. application of 360 mg/kg NMF with the intermittent s.c. injection of 720 mg/kg NMF with an interval of 48 h in P 388 leukemia showed that the daily application of NMF induced an increase of life span of 82% whereas the intermittent schedule effected a 142% increase of life span. The simultaneous combination of 360 mg/kg NMF with 60 mg/kg sodium ascorbate applied daily caused a 133% increase of life span and the simultaneous combination of 360 mg/kg NMF with 30 mg/kg menadione sodium bisulfite lead to a 126% increase of life span. The combined daily s.c. application of 360 mg/kg NMF with 30 mg/kg pyridoxal hydrochloride induced only a minimal difference compared to the daily application of 360 mg/kg NMF alone. The combination of 720 mg/kg NMF with 120 mg/kg sodium ascorbate applied in intervals of 48 h showed a 164% increase of life span. In advanced M 5076 sarcoma the daily s.c. application of 360 mg/kg NMF effected a 82% increase of life span and the combination of 360 mg/kg NMF with 60 mg/kg sodium ascorbate effected a 135% increase of life span.

Topics: Animals; Antineoplastic Agents; Ascorbic Acid; Drug Synergism; Female; Formamides; Leukemia P388; Life Expectancy; Mice; Pyridoxal; Sarcoma, Experimental; Vitamin K; Vitamin K 3

In rats and in humans, dimethylformamide (DMF) is mainly metabolized into N-hydroxymethyl-N-methylformamide (DMF-OH). The in vitro oxidation of DMF by rat liver microsomes is decreased in the presence of catalase and superoxide dismutase. The radical scavengers, dimethylsulfoxide (DMSO), tertiary butyl alcohol (t-butanol), aminopyrine, hydroquinone and trichloroacetonitrile reduce the oxidation of DMF to DMF-OH in vitro and in vivo. Conversely, DMF inhibits the demethylation of DMSO, t-butanol and aminopyrine. The addition of iron-EDTA to the incubation system induces the production of N-methylformamide (NMF) from DMF. These results support the hypothesis that the metabolic pathway leading from DMF to DMF-OH and NMF involves hydroxyl radicals. Superoxide radical and hydrogen peroxide take part in the metabolic process. DMF is preferentially metabolized into DMF-OH. NMF appears mainly when the production of hydroxyl radicals is stimulated, the methyl group being recovered as formic acid.

Topics: Animals; Ascorbic Acid; Biotransformation; Dimethylformamide; Edetic Acid; Ferric Compounds; Formamides; Formates; Free Radicals; Hydroxides; Hydroxyl Radical; Hypoxanthine; Hypoxanthines; In Vitro Techniques; Male; Microsomes, Liver; Oxidation-Reduction; Rats; Rats, Inbred Strains; Xanthine Oxidase