Protection of Hepatotoxic and Lethal Effects of CCl by Partial Hepatectomy

Abstract

CCI, is a hepatotoxic haloalkane, capable of producing hepatocellular fatty degenention and centrilobular necrosis. Previous reports indicate induction of liver regeneration after 3 6 4 8 hr of CCI, treatment, which is considered as a secondary effect. The present investigation was undertaken to evaluate the primary effects of CCI, on hepatic DNA synthesis and to correlate liver regeneration with CCI, toxicity. These studies were conducted in normal and actively regenerating livers using male Spngue-Dawley rats undergoing sham operation (SH), or partial (70%) hepatectomy (PH). Incorporation of 'H-thymidine ('H-T) in hepatocellular nuclear DNA and autoradiographic analyses of liver sections served as indices for hepatocellular regeneration. Initial experiments established that peak regeneration occurs at 2 days post-PH (PH,) and liver regeneration phases out by 7 days post-PH (PH,). SH and PH rats were challenged with a single ip dose of either corn oil vehicle or CCI, at either 0.1 mVkg (to represent subtoxic dose) or 2.5 mVkg (to represent toxic dose). The low dose of CCI, was not toxic and did not alter 'H-T incorporation and percentage labelled cells at 6 or 24 hours after administration to SH, PH, or PH, groups, indicating that there was no interference with PHstimulated hepatocellular regeneration. The high dose of CCI, was significantly hepatotoxic and lethal in SH rats, while in PH, rats both hepatotoxic and lethal effects were significantly decreased. 'H-T incorporation as well as percentage labelled cells, highly stimulated by PH, were significantly decreased by high dose of CCI,. However, hepatocellular regeneration in PH2 rats treated with high dose of CCI, was still significantly higher than SH or PH, groups by virtue of the stronger stimulatory effect of PH. In PH, nts, where hepatocellular regeneration had returned to the SH level, the hepatotoxic and lethal effects of the large dose of CCI, were also restored. These findings show that the progressive phase of a single high dose of CCI, injury which normally culminates in hepatotoxic and lethal eKects is significantly mitigated by previously stimulated hepatocellular regeneration. High dose of CCI, suppresses hepatocellular regeneration at early time points after administration in contrast to the smaller subtoxicdose ofCCI,. By virtue ofthe much stronger stimulatory effect, PH results in the protection against the hepatotoxic and lethal effects of CCI, despite the obtunding effects of the high dose on hepatocellular regeneration.

Upregulation of calpastatin in regenerating and developing rat liver: Role in resistance against hepatotoxicity

“…In contrast, if the rats are exposed to the same dose of CCl 4, 7 days post-PH when cell division has tapered off, injury progresses rapidly, liver fails, and the rats die, signifying complete loss of protection. 12,13 CAST expression data obtained in the current study coincide very well with these survival versus death observations reported earlier. 11 These findings are consistent with the notion that CAST overexpression may be the underlying mechanism of resiliency of the dividing/newly divided hepatocytes.…”

“…22,48 Partial hepatectomy, the second model of liver cell division studied in the current investigation, is known to protect the experimental animals from hepatotoxicity. [11][12][13] However, the time of exposure of PH animals to the toxic insult is pivotal in determining whether the final outcome is favorable. 12,13 If the PH rats are exposed to model hepatotoxicant CCl 4 at the time of peak liver regeneration (from 2 to 4 days after PH), progression of injury is substantially lower, leading to recovery from liver injury and animal survival.…”

“…[11][12][13] However, the time of exposure of PH animals to the toxic insult is pivotal in determining whether the final outcome is favorable. 12,13 If the PH rats are exposed to model hepatotoxicant CCl 4 at the time of peak liver regeneration (from 2 to 4 days after PH), progression of injury is substantially lower, leading to recovery from liver injury and animal survival. In contrast, if the rats are exposed to the same dose of CCl 4, 7 days post-PH when cell division has tapered off, injury progresses rapidly, liver fails, and the rats die, signifying complete loss of protection.…”

“…[4][5][6][7][8] Monitoring the markers of liver regeneration in drug overdose victims has been proposed as a prognostic predictor. 5 Under a variety of circumstances in which liver regeneration is stimulated experimentally either by chemical injury (e.g., low dose of thioacetamide, APAP) [6][7][8][9][10] or by surgical resection (two-thirds partial hepatectomy), [11][12][13][14] the liver is known to exhibit resistance toward the higher doses of the hepatotoxicants. Liver cell division during postnatal development in newborns is known to impart resistance against toxicity.…”

Hepatoprotective Effects of Mushrooms

“…The liver also plays an important role in drug elimination and detoxification and liver damage may be caused by many xenobiotics, such as alcohol and many medicines, malnutrition, infection, and anaemia [24,25]. Liver damage is a widespread disease which, in most cases, involves oxidative stress and is characterized by a progressive evolution from steatosis to chronic hepatitis, fibrosis, cirrhosis and hepatocellular carcinoma [26].…”