Inhibitory effect of chlormethiazole on the toxicokinetics of diethylnitrosamine in normal and hepatofibrotic rats

Abstract

The effect of chlormethiazole (CMZ) at single and multiple doses on the toxicokinetics of diethylnitrosamine (DEN) was investigated in normal rats and those with DEN-induced liver fibrosis. Twelve rats were treated with DEN (50 mg/kg) alone and in combination with a single dose of CMZ (10, 50, or 100 mg/kg) by intraperitoneal (i.p.) injection. In a multiple dose test, six rats were treated with CMZ (50 mg/kg) for 7 d with addition of DEN (50 mg/kg) on days 1 and 7. Lastly, 12 rats were treated with DEN (50 mg/kg) by i.p. injection twice a week for 4 consecutive weeks, followed by weekly injections for another 8 weeks to build the model of liver fibrosis. Following this induction, the 12 rats were given CMZ (50 mg/kg) combined with DEN (50 mg/kg) to study the inhibitory effect of CMZ on DEN metabolism in hepatofibrotic rats. Serial blood samples were also collected and analyzed by a validated high-performance liquid chromatography (HPLC) method. A single-dose CMZ treatment decreased DEN clearance (CL), prolonged the t, and increased the 'area under the curve' (AUC) for DEN in normal and hepatofibrotic rats relative to rats that did not receive CMZ. Treatment with CMZ for 7 d further prolonged the t for DEN but did not alter the CL and AUC relative to a single CMZ treatment. These results suggest that CMZ significantly inhibits the metabolism of DEN in normal and hepatofibrotic rats.

The POR rs10954732 polymorphism decreases susceptibility to hepatocellular carcinoma and hepsin as a prognostic biomarker correlated with immune infiltration based on proteomics

“…This affects the activities of CYPs including CYP2E1, and the important role of CYP2E1 in the activation of procarcinogens and protoxins. This speculation is supported by previous reports from other groups [ 9 , 35 – 39 ] as well as ours [ 16 , 17 , 40 ] that increased CYP2E1 activity is closely associated with oxidative stress, inflammation, and inflammation-related diseases like nonalcoholic steatohepatitis (NASH), hepatofibrosis, HCC, ovarian cancer, and so on.…”

From hepatofibrosis to hepatocarcinogenesis: Higher cytochrome P450 2E1 activity is a potential risk factor

“…To study the relationship between the inhibition of CYP2E1 activity at the hepatofibrosis stage and hepatocarcinogenesis, eight hepatocarcinogenesis model rats received chlormethiazole (CMZ, TCI (Shanghai) Development Co., Ltd.), a CYP2E1 inhibitor, by intraperitoneal injection at 100 mg/kg, 12 hepatocarcinogenesis model rats received an equal volume of saline by intraperitoneal injection and served as a control group. When DEN (50 mg/kg) was given together with CMZ or saline, DEN was administered immediately after the injection of saline or CMZ.…”

High CYP2E1 activity aggravates hepatofibrosis by limiting macrophage polarization towards the M2 phenotype

“…By comparing the physiological and pathological activity of CYP2E1, we previously found that CYP2E1‐mediated probe clearance increased remarkably in hepatofibrotic tissue and positively correlated with enzyme velocity for DEN metabolism. CYP2E1‐mediated probe drug clearance showed intraindividual variation in patients with hepatofibrosis, and the difference in the metabolism of DEN by CYP2E1 may be the cause of hepatofibrosis . Herein CYP2E1 activity was determined by measuring the enzyme velocity for DEN metabolism in human hepatofibrotic tissue.…”

“…Herein CYP2E1 activity was determined by measuring the enzyme velocity for DEN metabolism in human hepatofibrotic tissue. We explored the role of CYP2E1 in hepatofibrosis in DEN‐induced rats, which leads to typical liver fibrosis and resembles human hepatofibrosis progression. Our results indicate that the CYP2E1 activity increased in hepatofibrotic tissue adjacent to HCC and had a broad and powerful profibrotic effect in DEN‐treated rats, which was ameliorated by the CYP2E1 inhibitor.…”

“…Similarly, clearance values were also determined in hepatofibrotic tissue from patients with HCC; activity for CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, and CYP3A4/5 decreased in hepatofibrosis, whereas CYP2C9 and CYP2D6 activity did not change . CYP2E1 activity increased significantly in patients with hepatofibrosis; note that CYP2E1 is able to metabolically activate diethylnitrosamine (DEN), a carcinogen that can cause hepatofibrosis and HCC It is of interest to determine if an increase in the activity of CYP2E1 induces hepatofibrogenesis; hence, we previously explored the relationship between CYP2E1 activity and hepatofibrosis using a DEN‐induced rat hepatofibrosis model. Our findings indicated that the high CYP2E1 activity was associated with a greater likelihood of hepatofibrosis .…”