FIG. 5.

Mechanism of protection by 4MP in APAP hepatotoxicity. 4MP has distinct mechanistic targets along the temporal course of APAP pathophysiology (D) when given either as a cotreatment (A–C) or post-treatment (E–G). When given together with APAP, 4MP predominantly protects by inhibition of P450-mediated generation of NAPQI. This is reflected in the significant protection against elevation in ALT (A) and formation of protein adducts (B) at 6 h. Since upstream events are blocked, there is also a complete attenuation of JNK activation seen after APAP at this time point (C). When given as a post-treatment 90 min after a 300 mg/kg dose, which corresponds to a time point after early JNK activation (D), robust attenuation of liver injury is evident at both 3 and 6 h post-APAP (E). While NAPQI adducts at 3 h are not significantly influenced by the delayed 4MP treatment (F), some effect is evident at 6 h, probably due to modulation of adduct clearance by autophagy. Since the post-treatment is subsequent to JNK activation, no significant effect is seen at the earlier 3-h time point (G), but the presence of 4MP prevents maintenance of JNK activation as evident in the protection seen at 6 h (G). Data adapted from Refs. (2, 3). 4MP, 4-methylpyrazole.