Acute liver injury is frequently associated with oxidative stress. Here, we investigated
the therapeutic potential of carbon monoxide releasing molecule A-1 (CORM A-1) in
oxidative stress-mediated liver injury. Overnight-fasted mice were injected with acetaminophen
(APAP; 300 mg/kg; intraperitoneally) and were sacrificed at 4 and 12 h. They showed
elevated levels of serum transaminases, depleted hepatic glutathione (GSH) and hepatocyte
necrosis. Mice injected with CORM A-1 (20 mg/kg) 1 h after APAP administration, had
reduced serum transaminases, preserved hepatic GSH and reduced hepatocyte necrosis.
Mice that received a lethal dose of APAP (600 mg/kg), died by 10 h; but those co-treated
with CORM A-1 showed a 50% survival. Compared to APAP-treated mice, livers from those
co-treated with CORM A-1, had upregulation of Nrf2 and ARE genes (HO-1, GCLM and NQO-1).
APAP-treated mice had elevated hepatic mRNA levels of inflammatory genes (Nf-kappa
B, TNF-alpha, IL1-beta and IL-6), an effect blunted in those co-treated with CORM
A-1. In tert-butyl hydroperoxide (t-BHP)-treated HepG2 cells, CORM A-1 augmented cell
viability, reduced oxidative stress, activated the nuclear factor erythroid 2-related
factor 2 (Nrf2) and anti-oxidant response element (ARE) genes. The molecular docking
profile of CO in the kelch domain of Keap1 protein suggested that CO released from
CORM A-1 mediated Nrf2 activation. Collectively, these data indicate that CORM A-1
reduces oxidative stress by upregulating Nrf2 and related genes, and restoring hepatic
GSH, to reduce hepatocyte necrosis and thus minimize liver injury that contributes
to an overall improved survival rate.