Kupffer cells (KC) and gut-derived bacterial endotoxin have been implicated in the aetiology of alcoholic liver disease. Using in vivo microscopic methods, we have shown that ethanol ingestion in mice causes a dose dependent increase in leucocyte adhesion and endothelial cell swelling in hepatic sinusoids. Activation of KC is elicited at low doses while depression occurs at high doses and with chronic exposure. The responses are exacerbated in the presence of endotoxaemia or sepsis and are not seen in endotoxin-resistant animals, implicating a role for endotoxin in the ethanol-induced inflammatory response. In addition, the responses are abolished with anti-TNF alpha suggesting that TNF alpha is a primary mediator of these events. Nitric oxide (NO) initially appears to play an important role in these events by stabilizing the TNF alpha-mediated hepatic microvascular inflammatory response to acute ethanol ingestion, thereby helping to protect the liver from ischaemia and leucocyte induced oxidative injury. Finally, an ongoing clinical study has confirmed a mild systemic endotoxaemia in patients hospitalized for alcoholic liver disease. All of these results support important roles for endotoxin, cytokines, nitric oxide and sinusoidal lining cells in the pathophysiology of liver injury resulting from ethanol alone or in combination with infection.
Cytochrome P450 2E1 (CYP2E1), an ethanol-inducible Chlormethiazole is a sedative and anticonvulsive drug used form of P450, is active in the metabolism of numerous comin the treatment of alcohol withdrawal. Because it had been pounds. 1 These include endogenous substrates such as acereported that chlormethiazole inhibits the alcohol-inducible tone, 2 organic solvents, 3 procarcinogens (e.g., nitrosacytochrome P450 2E1 in rat liver, we investigated the in vivo mines), 4,5 and therapeutic agents such as chlorzoxazone, 6and in vitro effect of this drug on cytochrome P450 2E1 in acetaminophen, 7 and anesthetics. 8 Induction of CYP2E1 after human beings. The activity of this cytochrome was assessed chronic ethanol consumption results in an enhanced metabousing chlorzoxazone as a probe. The 6-hydroxychlorzoxalism of these xenobiotics, which is frequently associated with zone-chlorzoxazone blood concentration ratio, reflecting increased toxicity. 3,9 Additionally, the metabolism of many the cytochrome P450 2E1 activity, was determined in 10 conof these compounds is inhibited in the presence of ethanol, trols and in 24 alcoholic patients who had entered a hospital because it competes at the CYP2E1 binding site. (CLM), a sedative, hypnotic, anxiolytic, and anticonvulsive remained low (0.049 { 0.01) even though chlormethiazole drug, widely used in Europe in the treatment of ethanol doses were gradually decreased. Pharmacokinetic studies in withdrawal states, 18 has been described as an inhibitor of controls showed that chlormethiazole-mediated inhibition CYP2E1 in rat liver. 19 Apart from the usefulness of CLM in was present even when chlormethiazole was not detectable the treatment of ethanol withdrawal, it may also reduce the in the blood. In addition, the effect of chlormethiazole on rate of formation of hepatotoxic compounds. Therefore, we cytochrome P450 2E1 was studied in vitro using human liver investigated the effect of CLM on CYP2E1 activity in human microsomes. Dixon plot analyses showed a noncompetitive beings. The effectiveness of chlorzoxazone (CHZ) as a inhibition (Ki Å 12 mmol/L). These data clearly show that CYP2E1 probe has been shown in vitro and in vivo, 6,20 and chlormethiazole is an efficient inhibitor of chlorzoxazone me-the measurement of in vivo CHZ hydroxylation to 6-hytabolism and thus of cytochrome P450 2E1 activity in human droxychlorzoxazone (6-OH-CHZ) has been proposed as a beings. Because cytochrome P450 2E1 induction after chronic reliable and highly specific marker of CYP2E1 activity in ethanol consumption has detrimental effects on the liver human beings. [21][22][23] In alcoholic patients, CYP2E1 induction through free radical formation, treatment of alcohol detoxifi-results in an increased CHZ oxidation that returns to control cation with chlormethiazole may be beneficial. (HEPATOLOGY values after 5-8 days of abstinence.24 Thus, CYP2E1 activity 1997;26:957-961.)was assessed in alcoholic patients admitted to a hospital for detoxification when treated either with CLM or with chlorazepat...
Background-Nonalcoholic steatohepatitis (NASH) develops in the absence of chronic and excessive alcohol consumption. However, it remains unknown whether moderate alcohol consumption aggravates liver inflammation in pre-existing NASH condition.
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