Hisato Homma

Intracellular Binding and Transport of Hormones and Xenobiotics by Glutathiones-Transferases

(1988). Intracellular Binding and Transport of Hormones and Xenobiotics by Glutathiones-Transferases. Drug Metabolism Reviews: Vol. 19, No. 3-4, pp. 305-318.

Characterization and Localization of Glutathione‐S‐Transferases in Rat Brain and Binding of Hormones, Neurotransmitters, and Drugs

Abstract: Rat brain glutathione‐S‐transferases are rich in Yb type subunits with major RNA transcripts coding for a relatively uncommon Yb3 form. The Yb‐containing isoenzymes of brain cytosol bind glucocorticoids and are covalently labeled with dexamethasone 21‐methanesulfonate. Certain neurotransmitters, hormones, and drugs, such as serotonin, dopamine, glucocorticoids, thyroxine, apomorphine, and benzodiazepine derivatives, are effective inhibitors of brain glutathione transferase activity. Immunocytochemical studies show that Yb forms are localized in ependymal cells, subventricular zone cells, astrocytes, tanycytes, and astrocyte foot processes on blood vessels, but Yb was not detected in oligodendrocytes or neurons. Based on their localization and binding properties, brain glutathione‐S‐transferases have the potential to function in intracellular binding of a variety of compounds and thereby govern their uptake and release in brain, transport to neurons, as well as in their detoxification.

Effect of transjugular intrahepatic portosystemic shunt formation on portal hypertensive gastropathy and gastric circulation

OBJECTIVES:The aim of this study was to investigate the effect of a transjugular intrahepatic portosystemic shunt (TIPS) on portal hypertensive gastropathy (PHG) and gastric hemodynamics.METHODS:A total of 16 patients with cirrhosis and portal hypertensive gastropathy were prospectively studied. Of these, 12 patients underwent TIPS for esophageal varices and four for refractory ascites. Gastric mucosal blood flow (GMBF) was assessed by laser Doppler flowmeter, and total blood flow (TBF) in submucosa and mucosa by near-infrared endoscopy. Portal venous pressure was obtained by a transducer during the TIPS procedure. The severity of portal hypertensive gastropathy was classified as none, mild, or severe. The examinations were performed before and 2 wk after the procedure.RESULTS:TIPS significantly reduced portal venous pressure. PHG improved in all four patients with severe PHG and in five of 12 patients with mild PHG after treatment. Gastric mucosal blood flow increased from 49.0 to 55.6 ml/min/100 g after TIPS. In contrast, TBF decreased from 0.35/s to 0.27/s after treatment. Liver function tests showed no significant changes before and after the procedure.CONCLUSIONS:It is considered that TIPS may have a beneficial effect on PHG at least for a short time. The mechanism by which PHG improves may be closely related to the improvement of the injured gastric perfusion in cirrhotic patients with PHG.

A novel arterial infusion chemotherapy for the treatment of patients with advanced pancreatic carcinoma after vascular supply distribution via superselective embolization

Patients with American Joint Committee on Cancer Stage IV advanced pancreatic carcinoma have been treated by systemic chemotherapy, intraarterial chemotherapy, radiation therapy, and multidisciplinary treatment using a combination of these. However, the outcome has not always been satisfactory. In the current study the authors describe the method and results of a new chemotherapy for advanced pancreatic carcinoma.

Mechanisms for increment of platelet associated IgG and platelet surface IgG and their implications in immune thrombocytopenia associated with chronic viral liver disease

In addition to hypersplenism, immunological destruction of platelets by elevated platelet associated IgG (PAIgG) and platelet surface IgG (PSIgG) has been proposed as a causative factor for thrombocytopenia in chronic liver disease (CLD), although the implication of PAIgG may be debatable since recent investigations on idiopathic thrombocytopenic purpura disclosed the fact that PAIgG largely relates to the intra-platelet IgG in alpha-granules and not to PSIgG. Further, with regard to the elevated PSIgG of CLD, characterization as to whether it mainly represents anti-platelet glycoprotein (GP) antibodies or IgG contained in the immune complex has not been elucidated. Thirty-seven patients with chronic viral liver disease (CVLD); 31 hepatitis C and 6 hepatitis B were included in this study. First we monitored the changes in levels of PAIgG, alpha-granule IgG, PSIgG and mean platelet volume (MPV) during the course of partial splenic arterial embolization (PSE). The elevated level of PAIgG decreased after PSE, paralleling that of alpha-granule IgG, while PSIgG showed no change; MPV decreased reciprocally with the increase of platelet count. These results indicate that the increment of PAIgG in CVLD may be caused by accelerated destruction of platelets; this generally evokes hyperproduction of large-sized thrombocytes, which have an increased capability to uptake circulating IgG. To characterize PSIgG, we then tested CVLD patients for antiplatelet GP antibodies and found only a 5.4% positivity. It was also found that circulating immune complex levels in CVLD patients were clearly elevated, correlating with the levels of PSIgG. Thus, it was surmised that immune complexes bound to the platelet surface, and not platelet specific GP antibodies, may be playing a crucial role in platelet destruction of CVLD, possibly through phagocytosis by macrophages.

A Phase I Trial of Arterial Infusion Chemotherapy with Gemcitabine and 5-Fluorouracil for Unresectable Advanced Pancreatic Cancer after Vascular Supply Distribution via Superselective Embolization

BACKGROUND We previously reported that arterial infusion chemotherapy improved the response rate and survival of the patients with pancreatic cancer at advanced stages in an open trial. We conducted a Phase I trial of arterial infusion chemotherapy with gemcitabine and 5-fluorouracil for advanced pancreatic cancer after vascular supply distribution via superselective embolization. METHODS Patients were treated after arterial embolization for hemodynamic change to restrict the blood flow into the pancreas (mainly to the great pancreatic artery and the caudal pancreatic artery). Arterial infusion chemotherapy consisted of gemcitabine in doses that were increased from 600 to 1000 mg/m(2) in subsequent cohorts on Day 1 plus continuous infusion of 5-fluorouracil 300 mg/m(2)/day on Days 1-5 every 2 weeks. Result Twelve patients were enrolled. The maximum tolerated dose of gemcitabine was determined to be Level 3 (1000 mg/m(2)). Only very mild hematological and non-hematological toxicities were noted. The overall response rate was 33.3%. The median survival time was 22.7 (95% CI; 9.5-24.5) months and the 1- and 2-year overall survival rates were 83.3 and 25.0%, respectively. CONCLUSION Arterial infusion chemotherapy using 1000 mg/m(2) gemcitabine on Day 1 and 300 mg/m(2)/day 5-fluorouracil on Days 1-5 every 2 weeks warrants a Phase II study.

Rheologic analysis of gastric mucosal hemodynamics in patients with cirrhosis

BACKGROUND Portal hypertensive gastropathy causes some gastric mucosal microcirculatory disorders in cirrhotic patients, but the nature of the rheologic dysfunction in the gastric microcirculation remains to be clarified. METHODS To examine the rheologic properties of the gastric microcirculation, we subjected 112 cirrhotic patients and 51 control subjects to endoscopic laser Doppler flowmetry and measured multiple variables of flow, red blood cell volume, and velocity. Furthermore, based on these results, we analyzed the shear rate which reflects the status of the microcirculatory system. To validate the laser Doppler flowmetry, we derived the relationship between red blood cell volume and cross-sectional areas of submucosal collecting venules; near-infrared endoscopy was used to evaluate this relationship. RESULTS Analysis of shear rate according to the severity of portal hypertensive gastropathy showed that the mucosa was exposed to strong hemokinetic stress in severe cases, characterized by a higher shear rate than in control subjects or in mild cases. Nitroglycerin, administered by intravenous infusion (1.0 microg/kg/min), reduced blood flow and restored shear rate to control levels in patients with severe portal hypertensive gastropathy. CONCLUSION This rheologic study of the gastric mucosa suggests that a disorder of the shear rate control mechanism in the microcirculation is associated with severe portal hypertensive gastropathy.

Advanced pancreatic carcinoma showing a complete response to arterial infusion chemotherapy

We report a patient with advanced carcinoma of the pancreatic body and tail with multiple liver metastases who showed a complete response to hepatic and splenic arterial infusion chemotherapy (HSAIC) with gemcitabine and 5-fluorouracil, following transcatheter peripancreatic arterial embolization (TPPAE) and partial splenic embolization (PSE). Nonresectable advanced pancreatic carcinoma tends to have a low response to medical treatment, with the median survival time being 6 months or less for stage IV cases. We disclose herein that the median survival time of patients receiving HSAIC after TPPAE is more than three times longer than the survival time attained with conventional treatments. However, in patients with advanced carcinoma of the pancreatic tail, for which TTPAE is not applicable, survival times remain low. Thus, in the patient described here, we also performed embolization of the left gastric and short gastric arteries as well as PSE to increase the flow within the great pancreatic and caudal pancreatic arteries via the splenic artery, and gemcitabine and 5-fluorouracil were administered via the splenic artery. As a result of these procedures, marked reduction in the advanced carcinoma of the pancreatic body and tail and of liver metastases was attained.

A case of successful management of portosystemic shunt with autosomal dominant polycystic kidney disease by balloon-occluded retrograde transvenous obliteration and partial splenic embolization.

We describe a patient with autosomal dominant polycystic kidney disease who was successfully managed for severe abdominal distension, impaired liver function and a portosystemic shunt by interventional therapies. The patients intra-hepatic portal vein was compressed and narrowed by multiple liver cysts, which resulted in a decrease of the portal blood flow and portal hypertension due to a huge gastro-renal shunt These haemodynamic changes were assumed to contribute to insufficient protein synthesis in the liver. Therefore, we first repeatedly performed minocycline hydrochloride instillations to treat the multiple liver cysts. Then, we conducted a partial splenic embolization to prevent elevation of the portal vein pressure prior to balloon-occluded retrograde transvenous obliteration which was performed to increase the portal blood flow. The portal blood flow markedly increased, and protein synthesis in the liver also recovered and the clinical symptoms improved. The patient has been monitored for more than two years up to the present and her liver function parameters have remained within the normal range. Renal insufficiency is known to be a major prognostic factor in autosomal dominant polycystic kidney disease. In some cases, however, liver involvement with multiple cysts may result in a fatal outcome. In such cases, interventional therapies, as provided to this patient, should be considered.

Re: Spontaneous rupture of renal metastasis of hepatocellular carcinoma: management by emergency transcatheter arterial embolization.

Spontaneous rupture of a primary lesion in hepatocellular carcinoma (HCC) is not unusual, and may be one of the defining factors in the prognosis [1]. However, rupture of an HCC metastatic lesion is very rare [2–4]. There are no reports in the literature describing cases with ruptured renal HCC metastasis. We report a case of massive retroperitoneal hemorrhage from the site of a right renal HCC metastasis. The bleeding was successfully controlled by transcatheter arterial embolization (TAE). In August 1997 a 67-year-old man with liver cirrhosis associated with hepatitis C virus had undergone TAE for an HCC in S1 measuring 3.5 3.8 cm. Following the first treatment, repeat TAE therapy was performed three times for recurrent HCC in S1. In December 1998, a chest X-ray showed lung metastasis in the right middle lobe, for which 48 Gy radiotherapy was performed. In January 1999, he was readmitted to our hospital with a chief complaint of severe headache. Brain computed tomography (CT) revealed a tumor in the left occipital lobe, suggesting HCC metastasis. He underwent surgery on the 4th hospital day. Histological examination of the tumor showed poorly differentiated HCC. He had no headache after the operation and was then discharged on the 15th hospital day. In March 1999, CT scan revealed new lesions in the bilateral kidney (Fig. 1A) and the left lung, suggesting HCC metastases. We decided that further treatment would be futile, so we followed him conservatively. On April 16, 1999, he was brought to our hospital by ambulance, presenting with right flank pain and hypovolemic shock. Abdominal CT scan showed a retroperitoneal hematoma in contact with the right kidney which was displaced ventrally (Fig. 1B). Enhancement with contrast material was seen in the hematoma, suggesting persistent bleeding. Three hours after the admission, emergency angiography was performed. A selective right renal arteriogram showed tortuous arteries and a 2-cm tumor at the lower pole of the right kidney (Fig. 2A), where extravasation of contrast material was observed. This suggested a tumor rupture causing continued bleeding. In order to achieve hemostasis, TAE was performed using Gelform and coils. A right renal arteriogram after TAE showed occlusion of the feeding artery to the tumor and preservation of normal renal parenchyma (Fig. 2B). Subsequently, his blood pressure stabilized and his general condition improved. Three months after TAE the patient died from recurrence of brain metastasis. Tumor rupture, however, never recurred. At autopsy we discovered HCC in the liver, bilateral lung, right parietal pleura, brain, spleen, and left kidney. The liver showed macronodular cirrhosis and a 3-cm diameter lesion of poorly differentiated HCC, exposed to the inferior vena cava, in S1 with necrotic tissue due to treatment. The tumor of the right kidney was thoroughly necrotic. All tumor cells found at autopsy had the same histological appearance as the primary tumor. Renal metastasis of HCC is often observed at autopsy, but it is rarely clinically diagnosed. Nakashima et al. [5] reported that extrahepatic metastasis was found in 144 (64%) of 225 autopsies in patients with HCC and renal metastasis in five (2.2%). Systemic metastasis was observed in our patient, probably because the HCC was exposed to the inferior vena cava and consisted of poorly differentiated cells, although primary HCC was localized in S1. Spontaneous rupture of primary HCC into the peritoneal cavity is reported to occur in 10% of cases [1]. In contrast, spontaneous rupture of metastatic lesions is very rare but has been previously reported in the lung, rib, spleen, pleura, and peritoneum [2–4]. All of these reported cases were treated conservatively and the patient died of hemorrhagic shock or hepatic failure. It is thought that massive hemorrhage may become one of the causes of hepatic failure in cirrhotic patients with ruptured HCC, who often have limited hepatic reserve for ischemia. An early diagnosis of the rupture site is required. In our case, dynamic CT scan showed the presence of the hematoma and active bleeding and was useful for an early diagnosis. Control of bleeding from a ruptured HCC is often difficult. Recently, several reports have described the usefulness of TAE, tolerable for patients with severe liver dysfunction in contrast to surgery, for the management of spontaneous rupture of primary HCC [6]. TAE is effective in achieving immediate hemostasis in almost all patients. Its immediate mortality rate is far less than that of surgery. As to the kidney, there have been many reports on the effectiveness of TAE for rupture of renal angiomyolipoma [7]. TAE is a minimally invasive therapy and can preserve the normal renal parenchyma by selective embolization of the feeding artery to the tumor. In conclusion, selective arterial embolization is an effective and safe procedure to manage tumor rupture. It is thought that TAE may be appropriate therapy even for ruptured renal HCC metastasis.