الفهرس 
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Abstract
Tuberculosis (TB) is one of the major infectious diseases threating
populations mainly in developing countries. Standard TB treatment consists
of a 6-month antibiotic course with isoniazid, rifampicin, pyrazinamide and
ethambutol or streptomycin. Previous studies showed that these drugs
induced hepatotoxicity.
The present study was conducted to evaluate the cytotoxicity study of
the drug complexes on HepG2 cell line model and to assess LD50 doses
,non toxic doses are used to study drug interaction on HepG2 cell line and
study the metabolic activity of these drug complexes on microsomes and
fresh isolated hepatocyte primary culture.
Data from the present study showed that the maximum drug
concentrations at which HepG2 cells were exposed to were 200 mM
Isoniazid, 100mM Hydrazine, 2mM Rifampicin and 200mM Pyrazinamide.
The LD 50 doses were 50 mM for Isoniazid, Hydrazine and Pyrazinamide
and 500μM for Rifampicin respectively. Rifampicin induced 50% mortality
at lethal dose (0.51 ±0.05) and Hydrazine induced 50% mortality at lethal
dose (29.6±1.4) this means that these antituberculosis drugs are more toxic
compared to Isoniazid which induced 50% mortality at lethal dose
(78.8 ±2.9) and Pyrazinamide which induced 50% mortality at lethal dose
(79.1 ±4.3) (Table, 2).
Pre-treatment with INH or RIF decreased the LD50 value of INH by
24.3% (P = 0.01) and 14.6% (P = 0.05), respectively, which means that in
vitro INH toxicity is increased by INH and RIF. HYD pre-treatment
decreased the INH LD50 by 25.9%, but only at border line statistical significance (P= 0.08). None of the pre-treatments had a substantial effect
on HYD or RIF toxicity. Pre-treatment with INH or HYD decreased the
LD50 of PZA by 30.2% (P = 0.02) and 38.1% (P = 0.02), respectively,
which means that in vitro PZA toxicity is increased by INH and HYD .
Pre-treatment with RIF decreased the LD50 value of INH by 74.2 %
which means that in vitro INH toxicity is increased by INH and RIF. HYD
pre-treatment decreased the INH LD50 by 72.2%, HYD decreased the
LD50 of PZA by 68% , respectively, which means that in vitro PZA toxicity
is increased by INH and HYD. None of the pre-treatments had a substantial
effect on HYD or RIF toxicity. These data are synchronized with
cytotoxicity assay.
Pre-treatment with RIF decreased the LD50 value of INH by 71.09 %
which means that in vitro INH toxicity is increased by INH and RIF. HYD
pre-treatment decreased the INH LD50 by 69.73%, HYD decreased the
LD50 of PZA by 67.4% , respectively, which means that in vitro PZA
toxicity is increased by INH and HYD. None of the pre-treatments had a
substantial effect on HYD or RIF toxicity. These data are synchronized with
cytotoxicity assay.
In conclusion, this study demonstrates that the in vitro hepatotoxicity
of Pyrazinamide is increased by pre-treatment with Isoniazide or its toxic
metabolite Hydrazine. This is another step in the understanding of the mechanism of Antituberculosis drug-induced hepatotoxicity.