Protective role of heme oxygenase-1 induction in carbon tetrachloride-induced hepatotoxicity

Abstract

Reductive metabolism of carbon tetrachloride (CCl(4)) is thought to cause lipid peroxidation which results in hepatic injury. Heme oxygenase-1 (HO-1) (EC 1.14.99.3), the rate-limiting enzyme in heme catabolism, is known to be induced by oxidative stress and to confer protection against oxidative tissue injuries. In this study, we examined the role of HO-1 induction in a rat model of CCl(4)-induced acute liver injury. CCl(4) treatment (1 mL/kg, intraperitoneally) produced severe hepatic injury in rats as revealed by significant increases in serum alanine transaminase (ALT) (EC 2.6.1.2) activity and hepatic malondialdehyde (MDA) content, severe liver cell injury, and increases in hepatic tumor necrosis factor-alpha (TNF-alpha) mRNA expression and DNA binding activity of nuclear factor-kappa B (NF-kappa B). Following CCl(4) treatment, hepatic HO-1 expression was markedly increased both at transcriptional and protein levels in hepatocytes, especially around the central vein. HO-1 induction was mediated in part through a rapid increase in microsomal free heme concentration presumably derived from hepatic cytochrome P450. Inhibition of HO activity by tin-mesoporphyrin (Sn-MP), which resulted in a sustained increase in microsomal free heme concentration, exacerbated liver injury, as judged by the sustained increase in serum ALT activity, extensive hepatocytes injuries, a more pronounced expression of hepatic TNF-alpha mRNA and an enhanced NF-kappa B activation. These findings indicate that induction of HO-1 is an adaptive response to CCl(4) treatment, and it may be critical in the recovery of hepatocytes from injury. Our findings also suggest that HO-1 induction may play an important role in conferring protection on hepatocytes from oxidative damage caused by free heme.

Opposite roles of neutrophils and macrophages in the pathogenesis of acetaminophen‐induced acute liver injury

“…On the contrary, we observed that APAP-induced liver injury was markedly attenuated in CXCR2-KO mice with reduced neutrophil infiltration, compared with WT mice, in line with previous reports that CXCR2-KO mice exhibited attenuated neutrophil infiltration in various disease models [16][17][18][19][20][21][22][23][24][25][26][27]. Indeed, Hogaboam and colleagues [38] observed that only a low level of CXCR2 was expressed on untreated hepatocytes and that APAP could enhance CXCR2 protein expression only transiently with a time lag.…”

“…We further showed that a substantial portion of macrophages expressed CXCR2 and that macrophages were a major source of heme oxygenase (HO)-1, which exhibits protective activities for various liver injuries including APAP-induced liver injury [27][28][29][30]. Thus, the present study implied that CXCR2 has double-edged roles in APAP-induced liver injury, by regulating the recruitment of both iNOS-expressing neutrophils and HO-1-expressing macrophages.…”

“…Because several lines of evidence suggest protective roles of HO-1 in experimental liver injury [27][28][29][30], we next examined the intrahepatic HO-1 gene expression. Before APAP injection, HO-1 mRNA was detected faintly but to a similar extent in the liver of all four groups.…”

Protective effects of naringenin-7-O-glucoside on doxorubicin-induced apoptosis in H9C2 cells

“…HO-1 overexpression could decrease apoptotic cell death by enhancing Bcl-2 and depressing caspase-3 expression (Wang et al, 2004). Induction of HO-1 by chemical inducers or selective overexpression is cytoprotective both in vitro and in vivo (Nakahira et al, 2003;Nath, 2006). In addition, it has been demonstrated that carbon monoxide might possess antiapoptotic properties (Brouard et al, 2000;Liu et al, 2003).…”

Sparassis crispaAttenuates Carbon Tetrachloride-Induced Hepatic Injury in Rats

“…However, the role of NF-κB in liver damage remains controversial. While it has been shown that NF-κB activation promotes cell survival in TNF-α-induced hepatotoxicity [26], studies have also indicated that NF-κB is an important regulator of numerous inflammatory mediators, several of which have been implicated in drug-induced hepatotoxicity [27,28]. On the basis of these observations, it is reasonable to speculate that Sparassis crispa may protect against hepatotoxicity by exerting anti-NF-κB actions.…”