Effect of isoniazid on glutathione biosynthesis and degradation in Mycobacterium smegmatis

The mechanism of glutathione (GSH) depletion by isoniazid (INH) was studied in M. smegmatis. INH increased the activity of gamma-glutamyl transferase (GGT) whether added before medium inoculation or to actively growing cells. The activity of GGT in cells grown from the beginning in INH-containing medium increased significantly on growth days 2-6. Three-day old M. smegmatis cells treated with INH exhibited a 30-65% increase in the activity of GGT. The activities of gamma-glutamyl-cysteine synthase (GGCS) and GSH synthase (GS) were lowered by 50 and 56% respectively on the second day of growth when M. smegmatis was grown in a medium supplemented with 1.5 mg INH per L. In 3-day old M. smegmatis, INH significantly inhibited the activities of GSH biosynthetic enzymes. The results demonstrate that the increased activity of GGT and decreased activities of GSH biosynthetic enzymes are responsible for GSH depletion by INH in M. smegmatis.