Inhibition of the alanine-alpha-oxoglutaric acid transaminase of pig-heart muscle by cyclic hydrazides.

8oNicotinic acid hydrazide (isoniazid) has antituberculous activity both in vivo and in vitro (Fox, 1951). In man its principal toxic effect, peripheral neuritis (Biehl & Vilter, 1954; Oestreicher, Dressler & Middlebrook, 1954), can be prevented by the concurrent administration of vitamin B. (pyridoxine) (Biehl & Vilter, 1954; Biehl & Nimitz, 1954). It is of interest to discover whether the specific anti-mycobacterial activity of isoniazid is related to its anti-vitamin B6 action. Inhibition by isoniazid ofthe growth ofa number of bacterial cultures has been demonstrated (Yoneda & Asano, 1953; Lichstein, 1955) as well as inhibition of pyridoxal phosphate-dependent decarboxylases (Davison, 1956; Hoare, 1956), and of transaminases from Mycobacterium tuberculo8i8 var. avium (Ito & Sugano, 1954) and the Bacille Calmette Gu6rin strain (B.C.G.) of tubercle bacilli (Sakai, 1954); reversal of this inhibition was reported by most of these authors. These observations, together with the similarity in the chemical structure of isoniazid and pyridoxal, suggest that isoniazid may compete with vitamin B6 in enzyme systems such as decarboxylases and transaminases which are dependent on this co-factor. This hypothesis is supported by the high antituberculous activity of 2-methylisoniazid, which closely resembles pyridoxal phosphate in structure, in contrast to the markedly lower efficiency of the 2-ethyl analogue, and the inactivity of the higher 2-alkyl compounds as well as of 3-methyland 2:5-dimethyl-isoniazid (Isler et al. 1955). Evidence for the reversal by vitamin B6 of the antituberculous activity of isoniazid in vitro is conflicting. Pope (1956) found that pyridoxal and pyridoxamine caused reversal of the antituberculous activity, but Oestreicher et al. (1954) obtained reversal only with pyridoxal. Boone & Woodward (1953) and Ungar, Tomich, Parkin & Muggleton (1954) failed to detect reversal by either compound. Failure to obtain reversal of the antituberculous activity in vivo by concurrent admin* Present address: Chemistry Department, University of Sydney, New South Wales, Australia.