Relationship of Pyridoxine and its Derivatives to the Mechanism of Action of Isoniazid.

Abstract

In most instances of metabolic antagonism the essential metabolite and the inhibitory agent have been similar in chemical structure. The structural appearance of isoniazid: lead to the speculation that its mode of action might represent interference with the utilization of nicotinamide or some other essential metabolite of similar structure. This report deals with the screening of certain vitamins, some of which are structurally similar to isoniazid, for possible isoniazid reversal.Materials and methods. The method chosen to study the mode of action of isoniazid was similar to that of hlcIlwain ( 1 ) , and Lampen and Jones (2 ) . \7arious organisms with known nutritional requirements were inhibited with the drug and reversal of the inhibition was initially attempted with nicotinic acid, nicotinamide, pyridoxine, thiamine, riboflavin, pantothenic acid, and p-aminobenzoic acid. Studies were later limited to pyridoxine and its derivatives when the initial results showed that only these compounds gave a competitive reversal of inhibition. The final steps were to study the effects on various species of Mycobacterium. No attempt was made to study any organism in any medium when a concentration of greater than M of the isoniazid was required for inhibition. The organisms employed in this study were obtained from the American Type Culture Collection, Washington, D.C., unless otherwise stated. Synthetic medita were used whenever possible to control the amount of essential metabolites present. Some comparisons were made between synthetic and nonsynthetic media and Table I lists the organisms, media, references, and the method of measuring and detecting growth. Lactobacillus plantarum (arabinosus) 17-5 was chosen because of its wide external *Work done under the auspices of the AEC. t Sandia Base with station at Los Alamos. $ Kindly supplied as Nydrazid by Squibb and Co., and as Rimifon by Hoff mann-LaRoche, Inc. nutritional requirements which included those of major interest, nicotinic acid and pyridoxine. I t also discriminates between pyridoxine and its derivatives, pyridoxal and pyridoxamine, the latter 2 being more active than pyridoxine as growth promoters. In all experiments using LactobaciElus changes in growth were observed grossly over 72 hours and the medium titrated for acid production at that time. Streptococcus pyogenes was used only because of its external pyridoxine requirement. Saccharomyces carlsbergensis was chosen because of its use in assay of vit.B6 and its uniform response to BG and its derivatives. Final turbidity readings for determination of growth were made after 18 hours incubation at 30°C. The effect of isoniazid inhibition was studied in relation to: the growth of 2 Escherichia coli strains which do not require added B6, one mutant strain of which requires nicotinic acid or its amide. The final turbidity readings were made after 18 hours incubation at 37°C. The E. coEi strains are similar to the Mycobacteyium which also have no external requirement for pyridoxine or its derivatives. Both are k...

On the pattern of change in peripheral nerves produced by isoniazid intoxication in rats

“…It became clear from the work of Biehl and Vilter (1954) that high doses of isoniazid (20 mg./kg./ day) regularly produced symptoms of neuritis in patients, that their excretion of vitamin B6 under isoniazid medication rose to three times the normal rate and that large doses of pyridoxine were fully protective against developing neuropathy. The action of isoniazid had already been shown to be competitive against the phosphorylation of pyridoxine and its inhibitory action upon microorganisms was competitively reversed, particularly by pyridoxamine and by pyridoxal (Boone and Woodward, 1953;Lichstein, 1955). The reason for the occurrence of only 40% incidence of neuritis in patients on a high daily dose of isoniazid became clear when it was shown by Biehl (1956; that, on the basis of finding a bimodal distribution of the percentage of administered isoniazid found free in the urine, patients could be divided into two clear groups, slow inactivators and rapid inactivators.…”

Effect of Hydrazides on Liver Alanine and Aspartate Transaminases and Lactate Dehydrogenase in Developing Chick Embryos1

“…The mechanism of the inhibition of pyridoxal phosphate-dependent enzymes by hydrazides; especially isoniazid, has been widely discussed by many authors. I t has been suggested that the inhibition by isoniazid is due to competition between pyridoxal and isoniazid, for there is a structural resemblance between these two substances and the inhibition is reversed in many cases by pyridoxal (YONEDA et al 1952, YONEDA and ASANO 1953, BOONE and WOODWARD 1953. VILTER et al (1954) and DAVISON (1956) have suggested that the inhibition of these enzymes by hydrazine derivatives is due to the formation of hydrazonic compounds with pyridoxal.…”

Inhibition of the alanine–α-oxoglutaric acid transaminase of pig-heart muscle by cyclic hydrazides

“…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-istration of vitamin B. in mice and guinea pigs has also been reported (Ungar et al 1954;Grunberg & Blencowe, 1955;Wasz-Hockert, McCune & Tompsett, 1956;Brun, Cayre & Viallier, 1954).…”