Genetic effects of drug interaction in tuberculosis patients and their fate.
In this paper we will discuss the genetic consequences of drug interaction in tuberculosis patients. Blood from tuberculosis patients was cultured before, during, and after withdrawal of therapy involving five different drug combinations of isoniazid (INH), thiacetazone (TAZ), para-aminosalicylic acid (PAS), and streptomycin (SM). The approaches used to detect DNA damage were chromosome aberrations and sister chromatid exchanges (SCEs). A total of 179 subjects were analyzed. In combination these drugs showed synergistic, additive, and antagonistic effects, though they were found to be nonclastogenic individually. Four of the drug combinations, INH + TAZ, INH + PAS, INH + TAZ + SM, and INH + PAS + SM, induced a significant increase in the frequency of aberrations, whereas INH + SM did not induce aberrations. In fact, SM appeared to reduce the frequency of aberrations. SCEs were increased in only two patients: one treated with INH + TAZ and the other with INH + PAS. The frequency of aberrations after withdrawal of therapy was decreased; it was slightly higher than the controls, though it was insignificant. The return to normalcy could be due to elimination of damaged cells or the repair of DNA in lymphocytes. Though the drug-induced aberrations do not persist after withdrawal of therapy, the chromosome damaging combinations of drugs should be used with caution, because the possibility of meiotic chromosome damage in germ cells (during therapy), which might be passed on to the next generation, cannot be ruled out.
D010131:Aminosalicylic Acid / Q000008:administration & dosage / Q000009:adverse effects; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000009:adverse effects*; D002478:Cells, Cultured; D002869:Chromosome Aberrations / Q000187:drug effects*; D003434:Crossing Over, Genetic / Q000187:drug effects*; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D006801:Humans; D007538:Isoniazid / Q000008:administration & dosage / Q000009:adverse effects; D008214:Lymphocytes / Q000166:cytology / Q000648:ultrastructure; D008677:Metaphase / Q000187:drug effects; D012854:Sister Chromatid Exchange / Q000187:drug effects*; D013307:Streptomycin / Q000008:administration & dosage / Q000009:adverse effects; D013828:Thioacetazone / Q000008:administration & dosage / Q000009:adverse effects; D014376:Tuberculosis / Q000097:blood; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy / Q000235:genetics*
D000995:Antitubercular Agents; D010131:Aminosalicylic Acid; D013828:Thioacetazone; D007538:Isoniazid; D013307:Streptomycin