Abstract
As a serious infectious disease, tuberculosis threatens global public health. Isoniazid is the first-line drug not only in active tuberculosis but also in its prevention. Severe hepatotoxicity greatly limits its use. Curcumin, extracted from turmeric, has been found to relieve isoniazid-induced hepatotoxicity. However, the mechanism of isoniazid-induced hepatotoxicity and the protective effects of curcumin are not yet understood completely. We established both cell and animal models about isoniazid-induced hepatotoxicity and investigated the new mechanism of curcumin against isoniazid-induced liver injury. The experimental data in our study demonstrated that curcumin ameliorated isoniazid-mediated liver oxidative stress. The protective effects of curcumin were demonstrated and confirmed to be correlated with upregulating SIRT1/PGC-1α/NRF1 pathway. Western blot revealed that while inhibiting SIRT1 by the siRNA1 (a SIRT1 inhibitor), the expressions of SIRT1, PGC-1α/Ac-PGC-1α, and NRF1 decreased, and the protective effect that curcumin exerted on isoniazid-treated L-02 cells was significantly attenuated. Furthermore, curcumin improved liver functions and reduced necrosis of the isoniazid-treated BALB/c mice, accompanied by downregulating oxidative stress and inflammation in liver. Western blot revealed that curcumin treatment activates the SIRT1/PGC-1α/NRF1 pathway in the isoniazid-treated BALB/c mice. In conclusion, we found one mechanism of isoniazid-induced hepatotoxicity downregulating the SIRT1/PGC-1α/NRF1 pathway, and curcumin attenuated this hepatotoxicity by activating it. Our study provided a novel approach and mechanism for the treatment of isoniazid-induced hepatotoxicity.