Prevention of halothane-induced hepatotoxicity by hemin pretreatment: protective role of heme oxygenase-1 induction

Reductive metabolism of halothane in phenobarbital-pretreated rats is known to increase free radical formation that results in hepatotoxicity. It also is associated with a marked induction of microsomal heme oxygenase-1 (HO-1), suggesting that there is an alteration in heme metabolism. In this study, we examined heme metabolism in rats pretreated with phenobarbital, followed by exposure to halothane-hypoxia. In this model, there was a significant decrease in microsomal cytochrome P450 content in the liver, followed by a rapid increase in free heme concentration and a decrease in the level of mRNA for the nonspecific delta-aminolevulinate synthase. A transient but dramatic induction of HO-1 mRNA and a prolonged induction of heat shock protein 70 mRNA also occurred. The HO-1 protein was detected principally in the hepatocytes around the central vein. Serum alanine transaminase (ALT) activity, an indicator of hepatic dysfunction, increased continuously throughout the experiment. Hemin pretreatment induced hepatic HO-1 with abrogation of the halothane-induced hepatotoxicity in this model, as judged by ALT activity and normal histology. Our findings in this study thus indicate that halothane-induced hepatotoxicity is due not only to its reductive metabolite formation, but also to an increase in hepatic free heme concentration, which is a potent prooxidant; HO-1 induction is an important protective response against such changes. This is also the first study to demonstrate that hemin pretreatment, which induces HO-1 prior to exposure to halothane, effectively prevents halothane-induced hepatotoxicity.     

Safety and efficacy of glucagon as a premedication for upper gastrointestinal endoscopy--a comparative study with butyl scopolamine bromide

BACKGROUND: Glucagon inhibits digestive motility and is used for endoscopic premedication; however, its effect on cardiopulmonary function during endoscopy has not yet been fully investigated. AIM: To clarify the efficacy and safety of glucagon compared with butyl scopolamine bromide as upper gastrointestinal endoscopy premedication. METHODS: Two hundred and forty consecutive patients over 40 years of age, referred for upper gastrointestinal endoscopy, without any complications, were studied. These patients were randomly premedicated with butyl scopolamine bromide (SC group) or glucagon (G group). Time course changes in blood pressure, arterial oxygen saturation, heart rate and the number of retching episodes during endoscopy were examined. The efficacy of glucose tablets after upper gastrointestinal endoscopy to prevent hypoglycaemia caused by glucagon was evaluated. Cardiopulmonary parameters were also examined in 77 complicated patients with glucagon premedication (GC group). RESULTS: A continuous increase in heart rate during upper gastrointestinal endoscopy was observed in the SC group, but not in the G and GC groups. Blood pressure, arterial oxygen saturation and number of retching episodes were not different between the groups. Hypoglycaemia-related symptoms were frequent in the G group without glucose tablets, but were prevented by the administration of glucose. CONCLUSIONS: Glucagon has a weaker effect on cardiopulmonary function during upper gastrointestinal endoscopy than butyl scopolamine bromide. Glucose administration prevents hypoglycaemia-related symptoms caused by glucagon.     

Catechol and hydroquinone have different redox properties responsible for their differential DNA-damaging ability.

We examined the redox properties of the "carcinogenic" catechol and the "noncarcinogenic" hydroquinone in relation to different DNA damaging activities and carcinogenicity using 32P-labeled DNA fragments obtained from the human genes. In the presence of endogenous NADH and Cu2+, catechol induces stronger DNA damage than hydroquinone, although the magnitudes of their DNA damaging activities were reversed in the absence of NADH. In both cases, DNA damage resulted from base modification at guanine and thymine residues in addition to strand breakage induced by Cu+ and H2O2, generated during the oxidation of catechol and hydroquinone into 1,2-benzoquinone and 1,4-benzoquinone, respectively. EPR and 1H NMR studies indicated that 1,2-benzoquinone is converted directly into catechol through a nonenzymatic two-electron reduction by NADH whereas 1,4-benzoquinone is reduced into hydroquinone through a semiquinone radical intermediate through two cycles of one-electron reduction. The reduction of 1,2-benzoquinone by NADH proceeds more rapidly than that of 1,4-benzoquinone. This study demonstrates that the rapid 1,2-benzoquinone two-electron reduction accelerates the redox reaction turnover between catechol and 1,2-benzoquinone, resulting in the enhancement of DNA damage. These results suggest that the differences in NADH-mediated redox properties of catechol and hydroquinone contribute to their different carcinogenicities.     

A case of severe acute hyperkalemia during pre-anhepatic stage in living-related liver transplantation

We reported a case of severe acute hyperkalemia during pre-anhepatic stage in living-related liver transplantation. The serum potassium concentration was elevated from 5.1 mmol.l-1 to 7.3 mmol.l-1 after hepatic artery ligation. Inspite of administration of diuretics, calcium and glucose-insulin, T wave on ECG was elevated and premature ventricular contractions occurred frequently. Finally, ventricular tachycardia occurred three times. After hepatic vein ligation, in anhepatic stage, serum potassium decreased gradually to 3.7 mmol.l-1 and arrhythmia disappeared. We consider that the main cause of hyperkalemia in this case is flowing out of potassium from the ischemic liver by surgical manipulation. It is necessary to take care of the change of serum potassium concentration not only in postreperfusion but also pre-anhepatic stage in living-related liver transplantation.     

Inhibitory effect of a selective cyclooxygenase-2 inhibitor on liver metastasis of colon cancer

COX-2 overexpression is recognized in various cancers, but the role of COX-2 in the progression of cancer, including the liver metastasis of colon cancer, is not clearly understood. We examined the role of COX-2 in the mechanism of liver metastasis of colon cancer, using a highly metastasizable colon carcinoma cell line, LM-H3. A COX-2 inhibitor, JTE-522, inhibited cell proliferation and invasion of LM-H3 in vitro and clearly reduced the number of metastatic nodules on the surface of nude mouse livers in vivo. We also examined the effects of JTE-522 on the production of growth factors and MMPs through the use of ELISA and gelatin zymography, respectively. JTE-522 downregulated PDGF production by LM-H3 but had no influence on VEGF production. JTE-522 also inhibited MMP-2 secretion by LM-H3. JTE-522 downregulated PGE(2) production, but the associated changes in PGE(2) did not affect PDGF and VEGF production by LM-H3. We conclude that JTE-522 downregulated the cell proliferation and invasive potential of LM-H3 by reducing the production of PDGF and MMP-2 and hypothesize that these inhibitory effects on the production of PDGF and MMP-2 can lead to inhibition of liver metastasis of colon cancer. These data indicate that the COX-2 inhibitor JTE-522 has a high potential for use as a clinical agent for the treatment of liver metastasis of colon cancer.     

Treatment of recurrent malignant supratentorial astrocytomas with carboplatin and etoposide combined with recombinant mutant human tumor necrosis factor-alpha

BACKGROUND: This study assesses the safety, tolerance and preliminary efficacy of combined treatment with carboplatin, etoposide and recombinant human mutant tumor necrosis factor-alpha (TNF-SAM2) for recurrent malignant supratentorial astrocytomas at first relapse. MATERIALS AND METHODS: Carboplatin was administered intravenously at a dose of 400 mg/m2 on Day 1, while etoposide was administered intravenously at a dose of 100 mg/m2 from Day 1 to Day 3 for 3 days. From Day 7, 80x10(4) U/m2 TNF-SAM2 was given intravenously for up to 5 injections for 2 weeks. Treatment was repeated every 8 to 12 weeks. RESULTS: Ten patients previously treated with surgery, radiation therapy and chemotherapy with a nitrosourea (ranimustine: MCNU) for malignant astrocytomas received this regimen for up to four cycles. Three patients with anaplastic astrocytomas, one patient with anaplastic oligoastrocytoma and 6 patients with glioblastomas (3 men and 7 women), aged 27 to 69 years, were eligible and were evaluated for response and toxicity. Grade 2 and 3 hematological toxicities occurred in 4 (40%) and 2 patients (20%), respectively. Grade 2 hepatic toxicity was observed in two patients. Of 9 evaluable patients, three (33%), including one glioblastoma, partially responded to the treatment (PR) with time to tumor progression (TTP) of 231, 121 and 57 weeks, respectively. Two patients had stable disease (SD), while 4 glioblastomas (44%) had progressive disease (PD) with TTP values of 11, 15, 6 and 12 weeks, respectively. CONCLUSION: These results suggest that combined therapy with carboplatin, etoposide and recombinant mutant TNF-alpha in this patient population seems to be safe and acceptable and may benefit those with recurrent anaplastic astrocytomas. These intriguing clinical observations warrant a properly stratified randomized trial to determine whether this approach can provide therapeutic benefits and improve survival.     

Genetic alterations in adenoma-carcinoma sequencing of intraductal papillary-mucinous neoplasm of the pancreas

We investigated the adenoma-carcinoma sequence in intraductal papillary-mucinous neoplasm from the aspect of genetic changes. The formalin-fixed paraffin-embedded tumors and surrounding normal pancreatic tissues from patients with 16 intraductal papillary-mucinous adenoma of the pancreas (IPMA) and 10 intraductal papillary-mucinous carcinoma of the pancreas (IPMC) were provided for DNA extraction after microdissection. SSCP-DNA sequencing analysis demonstrated K-ras mutations at codon 12 in 75% of IPMA and 70% of IPMC, while those at codon 13 were observed neither in IPMA nor IPMC. There were no characteristic K-ras mutation types in IPMA and IPMC and no significant differences in incidence of K-ras mutations between the two categories. The frequencies of p53 mutations analyzed by SSCP-DNA sequencing were not high in IPMA (18.8%) and IPMC (30%), showing no significant difference between them. LOHs of APC in IPMA and IPMC were infrequent (6.3 and 20%, respectively) and showed no significant difference in incidence between the two categories. The LOH frequencies of DCC in IPMA and IPMC were 31.3 and 40%, respectively, and were not statistically different from each other. Taken together, genetic changes such as K-ras, p53, APC and DCC mutations may not be associated with adenoma-carcinoma sequence in intraductal papillary-mucinous neoplasm of pancreas.