The role of mdr2 in manganese-bilirubin induced cholestasis in mice.

The pathogenesis of manganese-bilirubin (Mn-BR) induced cholestasis has only been studied in rats and is associated with alteration in the hepatic homeostasis of cholesterol and phospholipids. Multidrug resistance-2 (mdr2) transporter, which mediates excretion of these lipids, is suggested to be involved in this phenomenon. The present study was undertaken to examine if Mn-BR induced cholestasis is reproducible in mice, then to clarify the role of mdr2 in its pathogenesis, using mice with disrupted mdr2 gene (mdr2 (-/-)).

Synergistic role of 3-hydroxy-3-methylglutaryl coenzyme A reductase and cholesterol 7alpha-hydroxylase in the pathogenesis of manganese-bilirubin-induced cholestasis in rats.

Manganese (Mn) and bilirubin (BR) induce intrahepatic cholestasis when injected sequentially. It was suggested that accumulation of newly synthesized cholesterol in the canalicular membrane is an initial step in the development of cholestasis. To clarify the involvement of cholesterol in the pathogenesis of Mn-BR-induced cholestasis, we examined biliary secretion and liver subcellular distribution of lipids in the cholestatic conditions (Mn-BR combination).

Simultaneous evaluation of HMG-CoA reductase and cholesterol 7alpha-hydroxylase activities by electrospray tandem MS.

Simultaneous evaluation of HMG-CoA reductase and cholesterol 7alpha-hydroxylase activities by electrospray tandem mass spectrometry (ES-MS-MS) was performed. The assay was based on the measurement of mevalonolactone (MVL) and 7alpha-hydroxycholesterol (7alpha-OHC) produced by the incubation of HMG-CoA with hepatic microsomes in the presence of NADPH and glucose-6-phosphate dehydrogenase. Following extraction and purification using a cyanopropyl cartridge, MVL and 7alpha-OHC were analyzed, without derivatization, by ES-MS-MS.

Role of perivenous hepatocytes in taurolithocholate-induced cholestasis in vivo.

The magnitude of cholestasis induced by taurolithocholic acid (TLCA) and its relationship with phase I metabolism were analyzed in rats treated with bromobenzene (BZ), a chemical that causes selective necrosis of perivenous (zone 3) hepatocytes. Forty-eight hours after BZ administration (600 mg/Kg bw), a single dose of 20 micromol/Kg bw of TLCA was injected. Bile was collected during 180 min and bile flow and total bile acid excretion rate were determined.

Chlorinated methanes and liver injury: highlights of the past 50 years.

The chlorinated methanes, particularly carbon tetrachloride and chloroform, are classic models of liver injury and have developed into important experimental hepatoxicants over the past 50 years. Hepatocellular steatosis and necrosis are features of the acute lesion. Mitochondria and the endoplasmic reticulum as target sites are discussed.

Manganese-bilirubin effect on cholesterol accumulation in rat bile canalicular membranes.

Manganese-bilirubin (Mn-BR)-induced cholestasis in rats is associated with altered lipid composition of various hepatic subcellular fractions. Increased bile canalicular (BCM) cholesterol content in Mn-BR cholestasis and the intracellular source of the accumulating cholesterol were investigated. To label the total hepatic cholesterol pool, male Sprague-Dawley rats were given ip 3H-cholesterol, followed 18 h later by 2-14C-mevalonic acid (a precursor of cholesterol synthesis).

Chloral hydrate enhances ethanol-induced inhibition of methanol oxidation in mice.

Several studies indicated that chloral hydrate can prolong the disappearance time of ethanol from blood in mice. This seems to result from inhibition of the enzyme alcohol dehydrogenase by chloral hydrate and trichloroethanol, its main metabolite. We examined the effect of both these compounds on the disappearance time of methanol in mice.

Effects of dexamethasone on functional and pathological changes in rat bronchi caused by high acute exposure to chlorine.

We assessed the effects of dexamethasone on functional and histological changes after acute exposure to a high level of chlorine gas in an animal model of reactive airways dysfunction syndrome (RADS). Sprague-Dawley male rats were exposed to 1500 ppm of chlorine for 5 min and treated with either dexamethasone (dex; 300 micrograms/kg/day) or saline intraperitoneally for 7 days. Lung resistance (RL), airway responsiveness to inhaled methacholine (MCh), airway wall morphometric measurements, and bronchoalveolar lavage (BAL) cells were assessed over a 2-week period after exposure.

Time-course of functional and pathological changes after a single high acute inhalation of chlorine in rats.

Reactive airways dysfunction syndrome (RADS) is an asthma-like condition that follows exposure to very high concentrations of an irritant material. We assessed the time-course of pathophysiological alterations in a model of RADS. Sprague-Dawley rats were exposed to 1,500 parts per million (ppm) of chlorine for 5 min.

Alteration of lipid composition of hepatic membranes associated with manganese-bilirubin induced cholestasis.

One hypothesis concerning the pathogenesis of manganese-bilirubin (Mn-BR)-induced cholestasis is that the molecular organization of the bile canalicular membrane is altered. The purpose of the present study was to evaluate lipid composition and fluidity of hepatic membranes during cholestasis in male Sprague-Dawley rats. To induce cholestasis, manganese (Mn, 4.

Altered cholesterol synthesis as a mechanism involved in methyl isobutyl ketone-potentiated experimental cholestasis.

Mechanisms by which ketones potentiate manganese-bilirubin (Mn-BR)-induced cholestasis are unknown. The purpose of the present study was to investigate the effect of methyl isobutyl ketone (MiBK), a widely used ketonic solvent, at the level of the bile canalicular membrane (BCM) and to verify if altered membrane lipid dynamics could be involved in MiBK-potentiated Mn-BR cholestasis. Male Sprague-Dawley rats were exposed 4 hr/day for 3 days to MiBK vapors (200 or 600 ppm).

Effect of dosing vehicle on the hepatotoxicity of CCl4 and nephrotoxicity of CHCl3 in rats.

There are conflicting results in the literature concerning the effect of gavage vehicle, corn oil (CO) versus aqueous suspension, on the toxicity of haloalkanes. The purpose of our study was to assess the influence of oral dosing vehicle on the acute hepatotoxicity of CCl4 and nephrotoxicity of CHCl3. Male Sprague-Dawley rats, fed ad libitum, were treated (po) with single doses of CCl4 or CHCl3 using corn oil (CO), or an aqueous preparation (5%) of Emulphor (EL620) or Tween-85 (Tw-85) as vehicle (10 ml/kg).

Ketone potentiation of intrahepatic cholestasis: effect of two aliphatic isomers.

Occupational exposure to methyl isobutyl ketone (MiBK) or methyl n-butyl ketone (MnBK) normally occurs by inhalation. The present study reports that exposure to both ketones can potentiate cholestasis experimentally induced by taurolithocholic acid (TLC, 30 mumol/kg) or by a combination of manganese (Mn, 4.5 mg/kg) and bilirubin (BR, 25 mg/kg).

Ketone potentiation of haloalkane-induced hepatotoxicity: CCl4 and ketone treatment on hepatic membrane integrity.

Previous results in male Sprague-Dawley rats indicate that acetone (A), methyl ethyl ketone (MEK), and methyl isobutyl ketone (MiBK) pretreatments (3 d, p.o.) at a dosage of 6.

Rat hepatocytes with elevated metallothionein expression are resistant to N-methyl-N'-nitro-N-nitrosoguanidine cytotoxicity.

Metallothionein (MT) is a small cysteine-rich metal-binding protein involved in Zn and Cu homeostasis as well as in heavy metal detoxication. It is also believed that when MT is overexpressed, it can confer resistance against alkylating agents. However, the mechanisms involved are still poorly understood.

Dose- and route-dependent alteration of metabolism and toxicity of chloroform in fed and fasting rats.

Effects of overnight food deprivation on the metabolism and toxicity of chloroform (CHCl3) administered to rats per os (po), intraperitoneally (ip), or by inhalation (inh) at different doses were investigated. Rats that had been either deprived of food overnight or normally fed were challenged with CHCl3 either po (0, 100, 200, or 400 mg/kg), ip (0, 100, 200, or 400 mg/kg), or inh (0, 50, 100, or 500 ppm for 6 hr). Overnight fasting increased CHCl3 metabolism in vitro about threefold with a decrease of liver glutathione content to 67%.

Ketone potentiation of haloalkane-induced hepato- and nephrotoxicity. II. Implication of monooxygenases.

Previous results in Sprague-Dawley rats indicate that acetone (A), methyl ethyl ketone (MEK), and methyl isobutyl ketone (MiBK) pretreatment (3 d, po) at dosages of 6.8 and 13.6 mmol/kg potentiate CCl4 hepatotoxicity and CHCl3 nephrotoxicity, respectively.

1-Naphthyl isocyanate and 1-naphthylamine as metabolites of 1-naphthylisothiocyanate.

The importance of the bioactivation of 1-naphthylisothiocyanate was studied. Forty minutes after 1-naphthylisothiocyanate administration to rats, bile was collected over a 2.5-h period; the liver was then excised and homogenized.

Ketone potentiation of haloalkane-induced hepato- and nephrotoxicity. I. Dose-response relationships.

Carbon tetrachloride (CCl4) induced hepatotoxicity and chloroform (CHCl3) induced nephrotoxicity were evaluated in male Sprague-Dawley rats pretreated with acetone (A), methyl ethyl ketone (MEK), and methyl isobutyl ketone (MiBK). Dose-response relationships for A, MEK, and MiBK potentiation of CCl4-induced hepatotoxicity and CHCl3-induced nephrotoxicity were compared. A, MEK, and MiBK pretreatment at a dosage of 6.

Induction of metallothionein gene expression by epidermal growth factor and its inhibition by transforming growth factor-beta and dexamethasone in rat hepatocytes.

Metallothionein (MT) is a small cysteine-rich protein thought to be mainly involved in metal regulation and detoxification. The implication of MT in cell growth and differentiation has also been suggested. This latter hypothesis was further investigated in adult rat hepatocytes induced to proliferate by epidermal growth factor (EGF).

Tissue concentrations of methyl isobutyl ketone, methyl n-butyl ketone and their metabolites after oral or inhalation exposure.

Quantitative relationships between plasma, liver and lung methyl isobutyl ketone (MiBK) and methyl n-butyl ketone (MnBK) concentrations after oral or inhalation exposure were established. Their respective metabolites (4-methyl-2-pentanol, 4-hydroxy-methyl isobutyl ketone, 2-hexanol, and 2,5-hexanedione) were also quantified. Male Sprague-Dawley rats were exposed for 3 days to MiBK or MnBK vapors (4 h/day) or treated orally for 3 days with a MiBK- or MnBK-corn oil solution.