Liver Toxicity of Thioacetamide is Increased by Hepatocellular Iron Overload

Abstract

An increase in hepatic iron concentration might exacerbate liver injury. However, it is unknown whether hepatic iron overload may exacerbate acute liver injury from various toxins. Therefore, we evaluated how manipulations to increase hepatic iron concentration affected the extent of acute liver injury from thioacetamide. In this study, we used rats with either "normal" or increased hepatic iron concentration. Iron overload was induced by either providing excess iron in the diet or by injecting iron subcutaneously. Both routes of providing excess iron induced an increase in hepatic iron overload. Meanwhile, the subcutaneous route induced both hepatocellular and sinusoidal cell iron deposition; the oral route induced lesser degree of hepatic iron concentration and only hepatocellular iron overload. Thioacetamide administration to the rats with "normal" hepatic iron concentration induced hepatic cell necrosis and apoptosis associated with a remarkable increase in serum aminotransaminases and depletion of hepatic glutathione and other antioxidative indices. Thioacetamide administration to the iron-overloaded rats exacerbated the extent of liver injury only in the rats orally induced with iron overload. In the rats subcutaneously induced with iron overload, the extent of liver injury from thioacetamide was not different from that observed in the rats with "normal" iron overload. It was concluded that the outcome of thioacetamide-induced acute liver injury may depend on both the level of hepatic iron concentration and on the cellular distribution of iron. While isolated hepatocellular iron overload may exacerbate thioacetamide-induced acute liver injury, a combined hepatocellular and sinusoidal cell iron deposition, even at high hepatic iron concentration, had no such an effect.

Early Detection of Acute Drug-Induced Liver Injury in Mice by Noninvasive Near-Infrared Fluorescence Imaging

“…To assess the potential benefit of combined screening for cell death, MMP activity, and transferrin receptor expression on the detection of DILI, we used fluorescent imaging probes specific for these biomarkers (AV-750, MMP-645, and TfV-750, respectively) to image the livers of animals receiving four different liver injury–inducing chemical compounds. Two of these compounds (TAA and APAP) are known to induce hepatocellular injury (McGill et al, 2012; Ackerman et al, 2015), a third drug (RMP) predominantly induces liver cholestasis (Zítková et al, 1982; Katz and Lor, 1986; Zargar et al, 1990), and a fourth drug (CPZ) induces mixed hepatocellular/cholestasis injury (Mullock et al, 1983). Serum ALT/ALP ratios can provide a rough mechanistic assessment, with hepatocellular injury defined as a ratio > 5, cholestasis as a ratio < 2, and mixed hepatocellular/cholestasis with a ratio between 2 and 5.…”

“…TAA is an organosulfur compound that has been used as a substitute for hydrogen sulfide, as a stabilizer of motor fuel, and as a topical preventative for mold growth on fruit. It is known as a class 2B carcinogen that also induces marked hepatocellular toxicity in animals (Wang et al, 2004; Ackerman et al, 2015). RMP is a widely used antimicrobial agent that is a crucial component in treatment regimens for tuberculosis.…”

Chemical induction of hepatic apoptosis in rodents

“…Compromised tissue repair in diabetic models highly influences TAA hepatotoxicity, as in streptozotocin (STZ)‐induced diabetic rats prolonged liver injury increases TAA hepatotoxicity (Wang, Fontenot, Soni, Bucci, & Mehendale, ). However, an in vivo study on rats showed that TAA toxicity could be exacerbated by hepatic iron overload (Ackerman, Pappo, Link, Glazer, & Grozovski, ).…”

The Effects of Chronic Iron Overload in Rats with Acute Acetaminophen Overdose

“…All rats were maintained on standard rat chow diet (SRCD; pellets #19520; Koffolk, Tel Aviv, Israel) and were given tap water to drink ad libitum. The composition of SRCD is reported elsewhere (Ackerman et al 2015).…”