Mode of Action of Isoniazid Viewed from Isotope Incorporation Studies

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There are many studies dealing with the mechanism of action of isoniazid; (1) pyridoxalcoenzyme inhibition; (2) TCA cycle inhibition; (3) dehydrogenase inhibition; (4) inhibition ofporphyrin metabolism; (5) inhibition due toperoxide production. However, there is no decisive elucidation to account for different observations presented. This study has been designedto present some findings through radioisotopeincorporation studies. Mycobacterium "Jucho" growing in Sauton.medium was washed in saline and used for experiments. Fractionation was conducted according to the procedure of Schneider. Concentration of isoniazid used was 10μg/ml throughoutthe experiments. 1) Incorporation of P32-orthophosphate intonucleic acid and protein fractions, especiallyinto the former, were inhibited significantly inthe presence of isoniazid. This inhibition increased after 3 hours of incubation (figures 1and 2 and tables 1 and 2). Since, as shownlater, incorporation of S35-sulfate was not inhibited and, in addition, the inhibition of the P32 incorporation was most significant not in allfractions but in the nucleic acid fraction, theinhibition of the p32 incorporation observed doesnot appear to be derived from an unspecific inhibition due to the general cease of cell function. It seems likely that the inhibition ofnucleic acid synthesis and protein synthesismay be a secondary effect due to an inhibitionof transaminase activity. Since a direct inhibition of transaminase by the drug requires toomuch amount of isoniazid to account for theantibacterial action of this drug, it appearsrather possible that disfunction of transaminaseis derived from a substitution of pyridoxalphosphate or pyridoxamine by isoniazid. Thispossibility remains to be studied in the future. 2) When P32-labeled cells were exposed toa P32-free phosphate solution, a considerableamount of P32 was released from cells. Declineof P32 compounds in the presence of isoniazidoccurred most significantly in the nucleic acidfraction (table 5). This finding shows thatphosphorus compounds incorporated into thenucleic acid fraction are not stabilized in thepresence of isoniazid. 3) Incorporation of S35-sulfate into differentcellular fractions were increased in the presenceof isoniazid. This suggests that an increase ofpermeability in cell membrane may be present (table 3). However, incorporation of S35 wasreduced in the presence of isoniazid after 22hours of incubation. The delayed decrease ofincorporation may be due to a general inactivation of cell functions. 4) Incorporation of Fe59C13 was inhibitedby the presence of isoniazid. However, theratio of distribution of Fe59 in cellular fractionsremained unchanged (table 4). Therefore, it islikely that the inhibition remains unspecific andis derived from a general inactivation of cellactivity. In summary: Incorporation of P32-phosphateinto the nucleic acid fraction and the proteinfraction, especially into the former, were inhibited by the presence of isoniazid (10μg/ml) Accordingly, it is conceivable that inhibition ofnucleic acid synthesis and protein synthesistake place in the presence of isoniazid. Thisinhibition does not appear to be an unspecificphenomenon derived from a general inactivationof cells. Incorporation of S35-sulfate is increased by the presence of isoniazid, suggesting thepresence of a change in permeability (changeof permeability seems to be some selective one, because incorporation of S35 is increased andthat of P32 is not increased).
一般社団法人日本結核病学会の論文

Mode of Action of Isoniazid Viewed from Isotope Incorporation Studies

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