Chlormethiazole inhibition of cytochrome P450 2E1 as assessed by chlorzoxazone hydroxylation in humans

Abstract

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...

Metabolism of bupropion by baboon hepatic and placental microsomes

“…The final concentration used for each inhibitor was approximately 10-fold its reported K i value to maintain selectivity for its specific CYP isozyme and to obtain at least ≥ 80% inhibition of the reaction. These inhibitors were dissolved in several solvents: 1) in 0.1M potassium phosphate buffer: quinidine, CYP2D6 (4µM) [15], chlomethiazole hydrochloride, CYP 2E1 (120 µM) [16], (+)-nootkatone, CYP2C19 (5µM) [17], phencyclidine hydrochloride, CYP2B6 (100µM) and ticlopidine hydrochloride, CYP2B6 (2µM) [18, 19]; 2) in 0.5% (v/v) ethanol: aminoglutethimide, CYP19 (7µM) [20], sulfaphenazole, CYP2C9 (3µM) [15], α-naphthoflavone, CYP1A1 (0.1µM) [15], ketonconazole, CYP 3A4 (1.8µM) [15] and furafylline, CYP1A2 (8µM) [15]; 3) in 0.3% (v/v) DMSO: trimethoprim, CYP2C8 (320µM) [21] and trans-2-phenylcyclopropyl-amine hydrochloride, CYP2A6 (0.4µM) [22]. Furafylline (the mechanism-based inhibitor) was pre-incubated with hepatic microsomes (0.25 mg) and the NADPH-regeneration system at 37°C for 10 min, and then 50 µM (≈ K m value) of bupropion was added to initiate the reaction.…”

Identification of cytochrome CYP2E1 as critical mediator of synergistic effects of alcohol and cellular lipid accumulation in hepatocytes in vitro

“…Of note, the joint effect of alcohol and cellular steatosis on autophagy required CYP2E1 activity in our in vitro model. Generally, this cytochrome P450 is known for its detrimental effects in alcoholic liver disease through free radical formation and lipid peroxidation [ 23 , 54 ]. Therefore, pharmacological inhibition of CYP2E1 has emerged as strategy for treatment of alcohol-induced liver injury [ 54 , 55 ].…”

Protective Effect of Chlormethiazole , a Sedative , against Acetaminophen - Induced Liver Injury in Mice

“…Chlormethiazole was reported to inhibit CYP2E1 transcription as well as CYP2E1 catalytic activity in humans 16 ) . However, one study performed in vivo in rats showed no significant effect of chlormethiazole on CYP2E1 catalytic activity, but showed selective transcriptional suppression of CYP2E1 26 ) .…”

“…At this dose, chlormethiazole nearly abolished acetaminophen-induced liver injury in mice. Since it was reported that a single administration of 192 mg of chlormethiazole in healthy human controls dramatically inhibits CYP2E1 catalytic activity 16 ) , the dose needed to prevent acetaminophen-induced liver injury may be within the usual therapeutic dose (1.5 g/d) in humans.…”

“…Chlormethiazole is a sedative and anticonvulsive drug widely used in the treatment of alcohol withdrawal in Europe. Recently, it was reported that chlormethiazole inhibits not only the CYP2E1 transcription but also the catalytic activity of the enzyme in humans 16 ) .…”