THE ROLE OF VITAMIN Be IN THE TOXICITY

Within recent years hydrazine and the methyl substituted hydrazines have come into considerable use as rocket fuels. As a result of this increased production of hydrazines, the possibility of accidental human exposure is of considerable interest. Obvious concern results from the fact that hydrazine had been used as an experimental means of producing fatty liver in experimental animals for many years. On an acute toxicity basis, O’Brien and coworkers (1964) reported comparative lethal dosebo ( LDSo) values for hydrazine 64 mg/ kg ( 2 mmoles/kg) , rnonomethylhydrazine (MMH) 28 mg/kg (0.61 mmoles/ kg), 1,l-dimethylhydrazine (unsymmetrical dimethylhydrazine, UDMH) 102 mg/kg ( 1.7 mmoles/ kg) , and 1 ,Zdimethylhydrazine (symmetrical dimethylhydrazine, SDMH) essentially nontoxic even at dosages of 500 mg/kg. The structures of these four compounds are shown in FIGURE 1, and it appears that a free amino group is essential for biological activity in this group of compounds. Barth and associates ( 1967) have previously reported the diuretic effect induced by UDMH, and it is interesting to note that of the four hydrazines shown in FIGURE 1, only SDMH is without diuretic effect, again emphasizing the biological activity of the free amino groups in this series of compounds. Killam and Bain reported in 1957 that thiosemicarbazide, furoyl hydrazide, and isonicotinic acid hydrazide would inhibit, in vitro, enzyme systems catalyzed by vitamin Bg. Thus it was suggested that the epileptiform convulsions produced by these compounds could be due to an inhibition of one or more of the enzyme systems requiring pyridoxal phosphate as a cofactor. In related findings, Reeves (1961 ) and Back and colleagues (1963) reported the use of pyridoxine and pyridoxamine as effective antidotes for UDMH and MMH toxicity. Similar findings on the effectiveness of pyridoxine in alleviating the convulsive symptoms of hydrazine toxicity have not been consistent. Medina ( 1963) reported that convulsions induced by hydrazine could be blocked by pyridoxine, but not by pyridoxal. O’Brien and associates (1964) reported that although hydrazine can be a convulsant at high doses, at doses near the LDJO it is not primarily a convulsant but is a depressant. On this basis, they suggest that hydrazine probably has a mode of action different from UDMH and MMH. It is interesting to note that this suggestion correlates with the early reports that brain levels of y-amino-butyric acid (GABA) are depressed after UDMH treatment but apparently elevated after hydrazine treatment.