Induction of Nrf2 and metallothionein as a common mechanism of hepatoprotective medicinal herbs.

Many Chinese medicines have the potential to be hepatoprotective and therefore can be used to treat acute and chronic liver diseases. The challenge is to identify the molecular target for their protective mechanism. This study investigated the induction of nuclear factor-erythroid 2(NF-E2)-related factor 2 (Nrf2) antioxidant genes and metallothionein as a common mechanism of hepatoprotective effects of Chinese medicines such as Piper puberulum. Mice were pretreated with Piper puberulum extract (PPE, 500 mg/kg, po) or vehicles for seven days, followed by intoxication with CCl 4 (25 µl/kg, ip for 16 h), D-galactosamine (800 mg/kg, ip for 8 h), or acetaminophen (400 mg/kg, ip for 8 h). Hepatotoprotection was evaluated by serum enzyme activities and histopathology. To determine the mechanism of protection, mice were given PPE (250-1000 mg/kg, po for seven days) and livers were collected to quantify the expression of Nrf2-targeted genes and metallothionein. Nrf2-null mice were also used to determine the role of Nrf2 in PPE-mediated hepatoprotection.PPE pretreatment protected against the hepatotoxicity produced by CCl 4, D-galactosamine, and acetaminophen, as evidenced by decreased serum enzyme activities and ameliorated liver lesions. PPE treatment increased the expression of hepatic Nrf2, NAD(P)H:quinone oxidoreductase1 (Nqo1), heme oxygenase-1 (Ho-1), glutamate-cysteine ligases (Gclc), and metallothionein (MT), at both transcripts and protein levels. PPE protected wild-type mice from CCl 4 and acetaminophen hepatotoxicity, but not Nrf2-null mice, fortifying the Nrf2-dependent protection. In conclusion, induction of the Nrf2 antioxidant pathways and metallothionein appears to be a common mechanism for hepatoprotective herbs such as PPE.

Ameliorative effect of an urinary preparation on acetaminophen and D-galactosamine induced hepatotoxicity in rats.

The effect of oral administration of a preparation of human urine (PHU) on acute liver injury was examined in rats intoxicated with acetaminophen and D-galactosamine. The results indicated that PHU protected the liver from acetaminophen and D-galactosamine-induced injury as judged by morphological and biochemical observation. An increase in lipid peroxide concentrations and decrease in protein concentrations occurred in the liver by D-galactosamine injection, PHU administration significantly prevented these changes.

[The effect of Essentiale and riboxin on the immunomodulating properties of the erythrocytes in a toxic liver lesion]. / Vliianie éssentsiale i riboksina na immunomoduliruiushchie svoistva éritrotsitov pri toksicheskom porazhenii pecheni.

D-galactosamine (DGA) increases the erythrocyte content of malonic dialdehyde (MDA) and the degree of peroxide hemolysis (DPH) of the erythrocytes, and reduces the 2,3-diphosphoglycerate (DPG) and ATP content. DGA induces the appearance of immunosuppressive properties in light erythrocytes. Essentiale (2 mg/kg) reduces the MDA content and DPH in the heavy erythrocytes and induces the appearance of immunostimulating properties in them. Riboxine (2 mg/kg) reduces the content of DPG and ATP in the light erythrocytes and prevents the appearance of immunosuppressive properties in them. Injection of 2 mg/kg of Essentiale or riboxine does not affect the development of the immune response induced by sheep erythrocytes in DGA poisoned rats. Combined injection of the compounds in a dose of 1 mg/kg intensifies the immune response of the poisoned animals.

[Lidocaine as an immunomodulator in a toxic liver lesion]. / Lidokain kak immunomoduliator pri toksicheskom porazhenii pecheni.

D-galactosamine (DGA) increases the malonic dialdehyde (MDA) content in the erythrocytes, reduces the ATP content, and induces the appearance of immunosuppressive properties in the red cells. Administration of lidocaine attenuates or completely removes these effects of DGA in poisoned animals. Extracorporeal treatment of the erythrocytes of intact rats with blood serum of DGA-poisoned reduces the ATP content and induces the appearance of immunosuppressive properties in the erythrocytes. Blood serum of DGA-poisoned rats which had been given lidocaine does not cause such effects.

Hepatic D-galactosamine toxicity studied with localized in vivo 31P magnetic resonance spectroscopy in intact rats.

Spatially resolved 31P magnetic resonance spectroscopy (MRS) at 4.7 T was applied to noninvasively assess liver phosphorus metabolites in a biochemically well-characterized model of hepatotoxicity induced by injection of a sublethal dose of D-galactosamine (galN). A newly developed hybrid method based on spectral localization with B0 and B1 gradients was employed to obtain multivoxel spectra in intact anesthesized rats. Spatially localized in vivo spectra were recorded 0 to 26 h after galN injection of female rats. In response to galN exposure, diphosphodiester peaks ascribed to UDP-hexosamines became detectable by 4 h and persisted up to 26 h. A metabolite coresonating with inorganic phosphate increased rapidly in intensity by 2 h after galN and returned to baseline by 18 h; this resonance was shown not to be Pi and was assigned to galN-1-phosphate by subsequent high resolution MRS experiments on extracts prepared from these livers. These results confirmed in vivo the metabolic perturbations described previously for this model of hepatotoxicity following biochemical studies based on classical extraction methods. Unlike the in vitro studies, however, these noninvasive experiments provided additional information on the time course of metabolic alterations on the same animal.

[The correction with hepatic protectors of structural metabolic disorders in the liver in D-galactosamine poisoning]. / Korrektsiia gepatoprotektorami strukturno-metabolicheskikh narushenii v pecheni pri intoksikatsii D-galaktozaminom.

The hepatoprotective agents silybinin, essentiale and eplir (the complex of phospholipids and caratinoids from the mud) prevent in D-galactosamine-induced intoxication of rats the development of hepatitis, hepatocyte necrosis, a decrease in hepatocytes of the activity of the enzymes of mitochondria and endoplasmic reticulum, labilization of lysosomes. These drugs stimulate D-galactosamine-suppressed antitoxic function of the liver: they increase the contents of RNA, cytochromes P-450, b5, the activity of amidopyrine-D-demethylase, hydroxylases of hexobarbital and aniline, improve the activity of the respiratory chain of microsomes, counteract inactivation of cytochrome P-450 into cytochrome P-420. Essentiale and eplir activate conjugation of xenobiotics with reduced glutathione.

Treatment of chronic liver injury in mice by oral administration of xiao-chai-hu-tang.

Oral administration of Xiao-Chai-Hu-Tang, the extract of a mixture of seven herbs, attenuated the hepatic fibrosis developed in mice after repeated doses of carbon tetrachloride. Its pre-administration reduced the derangement of liver function tests seen after a single dose of carbon tetrachloride as well as that seen after d-galactosamine intoxication. Xiao-Chai-Hu-Tang may be effective in the treatment of chronic liver injury through hepatocytoprotection.