Silymarin pre-exposure modulates oxidative stress and Bcl-XL expression in the liver and prevents doxorubicin-induced apoptotic and necrotic cell deaths

The emergence of silymarin (silbinin) as a natural remedy for liver diseases and its possible entry into the clinical trial testifies to its anti-hepatotoxic potential. At the molecular level, silymarin (SMN) has been vouched for by its ability to interfere with apoptotic signaling pathways while simultaneously acting as a powerful antioxidant. Although DOX is a cardiotoxin, this in vivo study explored whether pre-exposures to nontoxic doses of SMN can: (i) prevent Doxorubicin (DOX)-induced hepatotoxicity, (ii) reduce DOX-induced free radical-mediated oxidative stress, (iii) modulate Bcl-XL expression and (iv) minimize DOX-induced apoptotic and necrotic liver cell deaths. A group of ICR mice (3 months old) were designated as ((1) Control, (2) DOX alone, (3) SMN alone, & (4) SMN+DOX). Groups 1 and 2 received saline injections, whereas groups 3 and 4 were orally gavaged SMN (16mg/kg body wt./day) for 12 days. On day-14, a LD50 dose of DOX was administered i.p. (60mg/kg) to groups 2 and 4, and all the animals were sacrificed 48 hours later. Analysis of serum and tissue biochemistry revealed DOX-alone caused frank liver injury (>50-folds ALT) coupled with massive oxidative stress (>20 folds), DNA fragmentation (>15 folds) and a substantial decrease in Bcl-XL expression. Decrease in Bcl-XL translated into an elevated apoptotic, necrotic and apocrotic cell deaths. Interestingly, SMN exposure prior to DOX dramatically reduced hepatotoxicity and the associated toxic events. SMN also impacted the influence of DOX on Bcl-XL and did not allow its expression to go below control level, which was mirrored in a clear-cut abolition of all forms of cell deaths in SMN+DOX livers. Overall, these results demonstrated that SMN may prevent toxic effects of a hydroxyl radical producing hepatotoxin (DOX), neutralize oxidative stress by acting as a powerful antioxidant, safeguard the integrity of the genome and antagonize both apopotic and necrotic cell deaths by influencing the expression of the antiapoptotic gene Bcl-XL in the liver in vivo.