Decrease in Cytochrome P4502E1 as Assessed by the Rate of Chlorzoxazone Hydroxylation in Alcoholics during the Withdrawal Phase

To evaluate cytochrome P4502E1 (CYP2E1) induction in alcoholics, the ratio of the concentrations of 6-hydroxychlorzoxazone (6-OH-CHZ) and chlorzoxazone (CHZ) was measured in blood 2 hr after CHZ ingestion using a HPLC method. This ratio was determined in controls and in alcoholic patients after 1, 2, 3, 4, 5, 8, and 21 days withdrawal. It was found to be 0.34 ± 0.03 in 30 controls and 1.05 ± 0.14 in 41 alcoholic patients within 2 days following ethanol withdrawal. This ratio decreased rapidly during withdrawal as attested by the short half-life of CYP2E1, which was found to be 2.5 days. Patients tested for CHZ metabolism after 8 or 21 days alcohol abstinence displayed the same ratio as controls [0.35 ± 0.03 ( n = 28) and 0.31 ± 0.03 ( n = 34), respectively]. No correlation was observed between γ-glutamyltransferase, carbohydrate-deficient transferrin values, the amount of alcohol consumed/day, and the 6-OH-CHZ/CHZ ratio. There was no influence of smoking on the rate of CHZ hydroxylation, because smokers displayed the same ratio as nonsmokers [0.33 ± 0.025 ( n = 62) and 0.33 ± 0.02 ( n = 30), respectively]. The CHZ hydroxylation ratio seems to be a good reflection of the hepatic and extrahepatic CYP2E1 activity in humans.     

氯唑沙宗对脑血管疾病引发呃逆的疗效观察

目的 :观察氯唑沙宗对脑血管疾病引发呃逆症的治疗效果 ,探讨呃逆的发病机理及氯唑沙宗的药理作用。方法 :对 5 0例经颅脑CT证实为脑出血或脑梗死的患者 ,随机分为治疗组 :口服氯唑沙宗 0 .4g/次 ,3次 /d ;对照组 :口服胃复安 10mg/次 ,3次 /d ,并记录两组患者的治疗效果。结果 :两组的显效率分别为 80 %和 2 5 % (P <0 .0 1) ,总有效率分别为 93.3%和 4 5 % (P <0 .0 1)。两组比较差别有显著意义。结论 :本研究提示氯唑沙宗对脑血管疾病所引发的呃逆症有良好的治疗效果 ,且毒副作用少 ,值得推广。     

Chlorzoxazone exhibits neuroprotection against Alzheimer’s disease by attenuating neuroinflammation and neurodegeneration in vitro and in vivo

Alzheimer’s disease (AD), a complex and an age-related brain disease, is induced by the accumulation of amyloid beta (Aβ) and neuroinflammation. Chlorzoxazone (CZ) is a classical FDA-approved drug, and shows anti-inflammatory effects. However, up until now, its regulatory role in AD has not been investigated. Therefore, in this study we attempted to explore if CZ could be an effective therapeutic strategy for AD treatment. At first, the in vitro study was performed to mimic AD using Aβ. We found that Aβ caused p65 nuclear translocation in both primary microglial cells and astrocytes, which were, however, restrained by CZ treatments. Meanwhile, CZ incubation markedly decreased the expression of pro-inflammatory cytokines including tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β). Aβ deposition was also markedly reduced in glial cells treated with CZ. Importantly, we found that glial activation and its-related pro-inflammation induced by Aβ led to obvious neurodegeneration and neuroinflammation, which were effectively attenuated by CZ pre-treatment in the isolated primary cortical neurons. Then, the in vivo study was performed using APP/PS1 mice with AD. Behavior tests showed that CZ administration effectively improved cognitive deficits in AD mice. Neuron death in hippocampus of AD mice was also inhibited by CZ. Aβ accumulation in brain was markedly decreased in CZ-treated AD mice. We finally found that hippocampal glial activation in AD mice was obviously blocked by CZ supplementation, along with remarkable decreases in TNF-α, IL-1β and p65 nuclear translocation. Together, these findings above demonstrated that CZ could inhibit glial activation and inflammatory response, contributing to the suppression of neurodegeneration and neuroinflammation. Therefore, CZ may be an effective therapeutic strategy for AD treatment.     

氯唑沙宗片留样观察值的统计分析

氯唑沙宗片（Ｃｈｌｏｒｚｏｘｚｚｏｎｔｚｂｌｅｔｓ）为中抠性肌肉松驰药，我国于１９８８年初由卫生部批准投产，质量标准暂定有效期１年半，经对试制样品的留样观察实验数据的统计分析，提示有效期可延至３年以上。     

Chlorzoxazone: a probe drug whose metabolism can be used to monitor toluene exposure in rats

In this study we investigated cytochrome P450 (CYP) 2E1 expression using a probe drug, chlorzoxazone (CZX), whose metabolism can be used to monitor toluene exposure in rats. The animals received an i.p. injection of toluene (0.25, 0.5 and 1 ml/kg) once a day for 3 days. The total CYP and CYP2E1 content and the aniline and CZX hydroxylase activity (V _max and CL_int) increased depending on the dose of toluene administered. At the highest concentration (128 mM) of diethyldithiocarbamate, a specific inhibitor of CYP2E1, the production of 6-hydroxychlorzoxazone (HCZX) in microsomes from toluene-treated rats was reduced by about 80%. The IC₅₀ values in microsomes from toluene-treated rats were between 3 and 5 μM. The production of HCZX and the activity of aniline hydroxylase in toluene-treated rats were correlated with the amount of rat CYP2E1 protein (r=0.88 and r=0.88, respectively). The elimination of CZX by toluene-treated rats was increased and the HCXZ production in the toluene-treated group was greater than that in the olive oil control group. The correlations between intrinsic clearance (CL_int: V _max/K _m) in vitro and total body clearance (CL_tot) of CZX hydroxylation and the elimination half-life (t _1/2) of CZX in vivo in toluene-treated rats were high (r=0.784, P < 0.001; r=−0.678, P < 0.001, respectively). In addition, the metabolic plasma HCZX/CZX ratio did not require multiple blood sampling and 2 h after CZX administration in vivo there was also a high correlation with CL_int (V _max/K _m) in vitro (r=−0.729, P < 0.001). In conclusion, these results demonstrate that CZX is a very good probe for monitoring induction in toluene-treated rats. Received: 28 September 1999 / Accepted: 10 January 2000