Inhibitory action of chloramine on formate-metabolizing system. Studies suggested by an unusual case record.
We previously reported on a patient exposed simultaneously to methyl chloride and chloramine gas who developed metabolic acidosis and permanent blindness [M. Minami et al., Hum Exp Toxicol 11: 27-34, 1992]. The case report suggested the possibility of potentiation of methyl chloride toxicity by chloramine. The potentiating mechanism was investigated by exposing mice to methyl chloride followed by ammonia chloramine, and then the level of formate in urine samples was measured with an enzyme coupling method to detect disturbance of formate metabolism. Mice dosed with 0.05 mL 1.0 mM chloramine after methyl chloride exposure excreted a significantly larger amount of urinary formate than mice treated with only methyl chloride. There was no difference in urinary formate levels between mice treated with only 0.05 mL 1.0 mM chloramine and those given only the vehicle (0.1 M phosphate buffer pH 6.0) for chloramine. The underlying biochemical mechanism of deterioration of formate metabolism was found to be the inhibition of the enzyme, N10-formyl tetrahydrofolate (N10-f-THF) dehydrogenase by 0.56-3.35 microM chloramine in the in vitro experiment using the purified enzyme. Positive control mice, given orally 0.1 mL 10% methanol in 0.1 M phosphate buffer (pH 6.0) excreted the same amount of urinary formate as those receiving 0.05 mL 1.0 mM chloramine after methanol administration. This was ascribed to the inhibitory effect of chloramine on formaldehyde dehydrogenase and depletion of substrate for further metabolism. The inhibition of the enzyme by chloramine (2.7-100.8 microM) was confirmed by in vitro experiments, using the purified enzyme, formaldehyde dehydrogenase.
Minami
M
M
Department of Hygiene and Public Health, Nippon Medical School, Tokyo, Japan.
Inagaki
H
H
Katsumata
M
M
Miyake
K
K
Tomoda
A
A
D000445:Aldehyde Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D002700:Chloramines / Q000633:toxicity*; D004357:Drug Synergism; D005574:Formate-Tetrahydrofolate Ligase / Q000378:metabolism; D005561:Formates / Q000378:metabolism* / Q000652:urine; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008737:Methyl Chloride / Q000633:toxicity; D051379:Mice; D008813:Mice, Inbred ICR; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000037:antagonists & inhibitors / Q000378:metabolism; D000099295:Formyltetrahydrofolate Dehydrogenase
D000445:Aldehyde Oxidoreductases; D002700:Chloramines; D005574:Formate-Tetrahydrofolate Ligase; D005561:Formates; D008737:Methyl Chloride; D000587:Oxidoreductases Acting on CH-NH Group Donors; D000099295:Formyltetrahydrofolate Dehydrogenase; C020145:formaldehyde dehydrogenase (glutathione); C030816:chloramine