[Show abstract][Hide abstract] ABSTRACT: 5-Fluorouracil (5-FU) chemotherapy is the first choice treatment for advanced hepatocellular carcinoma (HCC), and resistance is the major obstacle to successful treatment. Recent studies have reported that epithelial-to-mesenchymal transition (EMT) is associated with chemoresistance in cancers. We speculated that EMT and 5-FU metabolism are related to the mechanism of 5-FU resistance. First, two 5-FU-resistant cell lines, HLF-R4 and HLF-R10, were established from the HLF undifferentiated human HCC cell line. Whereas cell growth was similar in the HLF and HLF-R cell lines, HLF-Rs are about 4- and 10-fold more resistant compared with the HLF cells; thus, we named these cell lines HLF-R4 and HLF-R10, respectively. The terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling assay also showed a dramatically decreased number of apoptotic cells in the HLF-Rs after treatment with 5-FU. We next assessed the characteristics of the HLF, HLF-R4 and HLF-R10 cells. Consistent with our hypothesis, the HLF-Rs had typical morphologic phenotypes of EMT, loss of cell-cell adhesion, spindle-shaped morphology and increased formation of pseudopodia. Real-time quantitative reverse transcriptase polymerase chain reaction data showed downregulated E-cadherin and upregulated Twist-1 and also indicated that EMT changes occurred in the HLF-Rs. We also found decreased ribonucleotide reductase and increased multidrug resistance protein 5 genes in the HLF-R cells. Our results suggested that the metabolism of EMT and 5-FU has important roles in 5-FU chemoresistance in the HLF-R cells, and that the HLF-R cells would be useful in vitro models for understanding the 5-FU-resistant mechanisms in HCC.
International Journal of Oncology 12/2011; 40(4):1005-10. · 2.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to evaluate the understanding and attitude of Japanese patients towards generic drug substitutions.
The subjects were male and female patients, who purchased their prescription medications at a pharmacy. A questionnaire was created to assess their attitudes towards generic drugs.
Of 1215 respondents, 68.4% knew the term "generic drugs." The majority of them had the correct understanding only on the following two points: generic drugs are less expensive than the brand name drugs (86.0%) and generic drugs contain the same active ingredients as brand name drugs (71.1%). However, their understanding was poor in other aspects of generic substitution: the availability and accessibility of generic drugs, etc. Only the experience of a previous generic drug substitution was significantly associated with the increased willingness for generic substitution (OR=2.93, CI 1.93-4.44). The main reasons for accepting generic substitutions were recommendations by physicians (48.6%) and by pharmacists (33.1%).
The public awareness program on generic drugs should be expanded to include more detailed information so that patients obtain the correct understanding of generic substitution. It is critical that physicians and pharmacists have the proper understanding of generic drug substitution and provide the correct information to patients.
Health Policy 01/2011; 99(1):60-5. · 1.51 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Aim The aim of this study was to evaluate Japanese community pharmacists’ attitudes toward and their recommendation of generic
substitution, and to identify the barriers towards performing generic substitution.
Subject and methods A questionnaire survey was conducted from June 2007 to December 2008. A total of 1,590 community pharmacists working for 449
community pharmacies whose owners agreed to participate in the study were involved in the study.
Results A total of 1,253 community pharmacists responded to the survey (response rate: 78.8%). The majority of respondents (72.1%)
were in favor of dispensing generic medicine, but they agreed that they would carefully decide if it is appropriate. In spite
of these favorable attitudes, more than half of the respondents (55.6%) seldom or never recommend generic substitution to
patients. Respondents indicated four barriers preventing them from performing generic substitution: (1) the generic drug is
not in stock or no generic drug equivalent is available yet in the market, (2) only a very small cost savings resulting in
patients’ objections, (3) physicians’ objections and (4) presence of skepticism in the quality of generic medicines and inadequate
drug information from generic manufacturers
Conclusion It is not common for Japanese community pharmacists to recommend generic substitution to patients in spite of their positive
attitudes towards generic substitution. Prospective policies on generic substitution are needed to overcome the barriers identified
in this study, preventing community pharmacists from performing generic substitutions.
Journal of Public Health 01/2011; 19(3):249-256. · 2.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study was undertaken to investigate the relationship between the plasma concentration of morphine, morphine-3-glucuronide and morphine-6-glucuronide and pain in cancer patients receiving oral morphine.
The trough value of plasma concentrations of morphine and its metabolites were measured by high performance liquid chromatography using an ultraviolet detector. Using this assay system, the plasma concentrations of morphine, morphine-3-glucuronide and morphine-6-glucuronide in 26 cancer pain patients were measured and compared with pain intensity. The pain intensity was assessed at the time of blood sampling using the visual analog scale.
The trough value of morphine and morphine-6-glucuronide did not show a significant correlation with pain intensity by visual analog scale assessment, but morphine-3-glucuronide and the ratio of morphine-3-glucuronide/morphine showed a significantly positive correlation (r = 0.528, P = 0.006 and r = 0.671, P < 0.001, respectively). By dividing the group according to low (≤ median value) or high (> median value) VAS scores a significant difference was found between the two groups in morphine-3-glucuronide and the ratio of morphine-3-glucuronide/morphine (P = 0.045 and P = 0.007, respectively).
These results indicated that the level of morphine-3-glucuronide is related to the patient's perception of morphine effect, and the plasma concentration of morphine-3-glucuronide and the ratio of morphine-3-glucuronide/morphine indicated potency to assess clinical effect.
International Journal of Clinical Pharmacy 12/2010; 32(6):737-43. · 0.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The evaluation of the progression of renal insufficiency, or decline in glomerular filtration rate (GFR), has been approached more simply and precisely by converting measured serum creatinine value into the reciprocal of serum creatinine, estimated GFR, or other parameters. Doubling of serum creatinine (simple doubling) is conveniently used as a surrogate endpoint for progression of renal disease but is thought to be biased unfairly by the initial value of serum creatinine (Scr(Int)). We proposed the definite decline in the reciprocal of serum creatinine (2-4 doubling) as a surrogate endpoint, comparing simple doubling with this new endpoint to verify the effect of Scr(Int) on the endpoint.
For the purpose of comparison between endpoints, 194 patients in a historical cohort of chronic glomerulonephritis were investigated. Kaplan-Meier survival analysis was performed with the composite endpoint of need for dialysis and either simple doubling or 2-4 doubling. Then, the distribution of Scr(Int) was compared between total patients and patients developing each endpoint.
The endpoint value of serum creatinine (Scr(End)) with 2-4 doubling was lower than that with simple doubling at Scr(Int) <2.00 mg/dl, and the difference of Scr(End) between simple doubling and 2-4 doubling was larger, as Scr(Int) became lower. In patients reaching simple doubling, Scr(Int) was higher than that of the total patients (1.66 vs. 1.07 mg/dl in median, respectively; p < 0.001). In patients reaching 2-4 doubling, there was no significant difference in Scr(Int).
Patients with low serum creatinine concentration at baseline had a tendency of prolonged development into simple doubling. In contrast, with 2-4 doubling, there was no bias of Scr(Int).
Clinical and Experimental Nephrology 11/2010; 15(1):100-7. · 1.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Collagen XVIII is a component of the highly specialized extracellular matrix associated with basement membranes of epithelia and endothelia. In the normal kidney, collagen XVIII is distributed throughout glomerular and tubular basement membranes, mesangial matrix, and Bowman's capsule. Proteolytic cleavage within its C-terminal domain releases the fragment endostatin, which has antiangiogenic properties. Because damage to the glomerular basement membrane (GBM) accompanies immune-mediated renal injury, we investigated the role of collagen XVIII/endostatin in this disorder. We induced anti-GBM glomerulonephritis in collagen XVIII alpha1-null and wild-type mice and compared the resulting matrix accumulation, inflammation, and capillary rarefaction. Anti-GBM disease upregulated collagen XVIII/endostatin expression within the GBM and Bowman's capsule of wild-type mice. Collagen XVIII/endostatin-deficient mice developed more severe glomerular and tubulointerstitial injury than wild-type mice. Collagen XVIII/endostatin deficiency altered matrix remodeling, enhanced the inflammatory response, and promoted capillary rarefaction and vascular endothelial cell damage, but did not affect endothelial proliferation. Supplementing collagen XVIII-deficient mice with exogenous endostatin did not affect the progression of anti-GBM disease. Taken together, these results suggest that collagen XVIII/endostatin preserves the integrity of the extracellular matrix and capillaries in the kidney, protecting against progressive glomerulonephritis.
Journal of the American Society of Nephrology 09/2010; 21(9):1445-55. · 8.99 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Renal anemia is a serious complication of chronic kidney disease (CKD) and accelerates its progress. Recombinant human erythropoietin (rHuEPO) therapy not only improves anemia but also has a renoprotective effect. This study aimed to determine whether treatment with rHuEPO can retard the initiation of hemodialysis (HD) in patients with CKD.
Clinical data of CKD patients who had already been treated with HD were analyzed retrospectively. Twenty-one patients who had received rHuEPO therapy constituted the treated group (EPO(+) group), and twenty-one other patients without rHuEPO constituted the non-treated group (EPO(-) group). The study start-point was the day of kidney function deterioration, judged as CKD stage 5. The end-point of the study was the initiation of HD.
During the evaluation period, mean values of hemoglobin (Hb) in the EPO(+) group remained lower than those in the EPO(-) group. Survival analysis limited to the two-year period from the beginning of evaluation showed that the renal survival rate of the EPO(+) group was significantly better than that of the EPO(-) group [EPO(+): 42.1% vs. EPO(-): 12.5%, p<0.05]. Duration of renal survival was 29.8 +/- 4.07 months in the EPO(+) group and 19.1 +/- 3.27 months in the EPO(-) group (p<0.05).
Although the mean values of Hb remained lower in the EPO(+) group than in the EPO(-) group during the observation period, the renal survival rate and duration of renal survival in the EPO(+) group were significantly superior than in the EPO(-) group. The study suggests that rHuEPO exerts a renoprotective effect via a mechanism other than the correction of anemia.
[Show abstract][Hide abstract] ABSTRACT: To assess the attitude of Japanese patients towards pharmacogenomics research and a DNA bank for identifying genomic markers associated with adverse drug reactions (ADRs) and their willingness to donate DNA samples, we conducted a survey of 550 male and female patients. The majority of the respondents showed a positive attitude towards pharmacogenomics research (87.6%) and a DNA bank (75.1%). The willingness to donate DNA samples when experiencing severe ADRs (55.8%) was higher than when taking medications (40.4%). Positive attitudes towards a DNA bank and organ donation were significantly associated with an increased willingness to donate. Though the level of positive attitude in the patient population was higher than that in the general public in our former study (81.0 and 70.4%, respectively), the level of the willingness of patients to donate was 40.4% when taking medications and 55.8% when experiencing severe ADRs which was lower than that of the general public in our former study (45.3 and 61.7%). The results suggested that the level of true willingness in the patient population was lower than that of the general public considering the fictitious situation presented to the public (to suppose that they were patients receiving medication). It is important to assess the willingness of patients who are true potential donors, not the general public.
Cell and Tissue Banking 12/2009; 12(2):71-80. · 1.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Aristolochic acid (AA) nephropathy, first reported as Chinese herbs nephropathy, is a rapidly progressive tubulointerstitial nephropathy that results in severe anemia, interstitial fibrosis and end-stage renal disease. Tubulointerstitial injury was studied in a mouse model of AA nephropathy to determine whether low-dose darbepoetin alpha (DPO) treatment prevents acute tubular necrosis and interstitial fibrosis.
AA was administered to C3H/He mice intraperitoneally and some mice were also treated with 0.1 microg/kg of DPO weekly starting on the day of AA administration or on day 28. At 28, 56 or 84 days, blood and urine samples were collected and mice were sacrificed for histological assessment of the kidneys.
AA-treated mice developed anemia, elevation of serum creatinine, severe tubular injury similar to acute tubular necrosis and progressive interstitial fibrosis. Although early treatment with low-dose DPO had minimal effects on the hematocrit, it significantly ameliorated acute tubular injury and interstitial inflammation through increasing the survival of tubular cells. As a result, it contributed to preservation of peritubular capillaries and reduction of interstitial fibrosis.
Low-dose DPO treatment conferred protection against acute tubular damage and attenuated interstitial fibrosis in a mouse model of AA nephropathy. Early administration of low-dose DPO may prevent the progression of acute tubular necrosis and the subsequent renal fibrosis in human AA nephropathy.
[Show abstract][Hide abstract] ABSTRACT: We found previously that increased levels of polyamine oxidase (PAO) [acetylpolyamine oxidase (AcPAO) plus spermine oxidase (SMO)], and acrolein (CH(2)CHCHO) are good markers of stroke. We then investigated whether silent brain infarction (SBI) can be detected by measuring acrolein, PAO, or other biomarkers. Several biomarkers were measured in the plasma of 53 normal subjects and 44 subjects with SBI. It was found that the levels of protein-conjugated acrolein (PC-Acro), interleukin-6 (IL-6) and C-reactive protein (CRP) were significantly higher in SBI than in normal subjects. PAO was slightly higher in SBI than in normal subjects. Since the probability of SBI was increased with age, values were analyzed including age as a factor. When the combined measurements of PC-Acro, IL-6 and CRP were evaluated together with age using a receiver operating characteristic curve, SBI was indicated with 89% sensitivity and 91% specificity. The results indicate that measurement of PC-Acro together with IL-6 and CRP makes it possible to identify SBI with high sensitivity and specificity.
[Show abstract][Hide abstract] ABSTRACT: Bupleuri radix is a commonly prescribed Oriental herbal medicine containing extracts of different Bupleuri species. We wished to determine whether two of these species, Bupleurum scorzoneraefolium and Bupleurum falcatum, or their active ingredients, saikosaponins a, c, and d, could prevent the development of immune-complex nephritis in nephrotoxic serum treated mice.
Immune-complex nephritis was created in C57BL/6 mice by administration of nephrotoxic serum containing anti-basement membrane antibodies. Mice were next given one of five treatments: Bupleurum scorzoneraefolium, Bupleurum falcatum, saikosaponin a, saikosaponin c, or saikosaponin d. Proteinuria, blood urea nitrogen, creatinine, and renal histological changes were then examined.
Saikosaponin c almost completely prevented the development of nephritis, although immune-complex deposition was not affected. Bupleurum falcatum and saikosaponin d had a significant, although lesser effect, and Bupleurum falcatum and saikosaponin a showed no effect.
The mechanism of action of saikosaponin c and the reasons for the difference between the two bupleuri species should be investigated further in order to find the best way to utilize the therapeutic effect of Bupleuri radix on nephritis.
Journal of Ethnopharmacology 04/2008; 116(3):397-402. · 2.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The information about a drug interaction is specified as a section which should be printed on the package insert in Japan, the U.S. and the U.K. In Japan, the information on drug metabolizing enzymes is described in the precautions for use in the package insert of many pharmaceutical agents following the incidence of the harmful effects of sorivudine. Since many elderly people suffer from two or more diseases as a result of aging and multiple pharmaceuticals are prescribed for them, the risk of drug interactions is increased. The therapeutic category where the most statements regarding drug metabolizing enzyme were in the package inserts, is hypnotics and sedatives, and anxiolytics; 100 out of 306 drugs include a statement about drug metabolizing enzymes. In the elderly aged 75 and over, regardless of whether the medicine is received in the hospital or by pharmacy preparation, in about 70 percent of the patients, three or more types of pharmaceutical agents are prescribed. Thus, although the information about the drug metabolizing enzyme is provided to the medical staff, in order to properly utilize the information, it is necessary to check whether the information about the same drug metabolizing enzyme is described in the package insert of the other pharmaceuticals that the patient is concurrently receiving. A means by which to quickly and easily retrieve the information about the drug metabolizing enzyme printed in the package is necessary and such a tool will be developed in the near future.
Yakushigaku zasshi. The Journal of Japanese history of pharmacy 02/2008; 43(2):175-80.
[Show abstract][Hide abstract] ABSTRACT: The levels of polyamines (putrescine, spermidine and spermine) and polyamine oxidase in plasma of patients with chronic renal failure were determined. The level of putrescine was increased but the level of spermine was decreased in the plasma of these patients. The patients also had increased plasma polyamine oxidase activity leading to increased degradation of spermine. As acrolein was a major toxic compound produced from spermine by polyamine oxidase, the levels of free and protein-conjugated acrolein in plasma were also measured. Acrolein levels were enhanced in plasma of patients with chronic renal failure. The accumulated acrolein found as protein conjugates was equivalent to 170 microM, which was about 5-fold higher than in plasma of normal subjects. It was found that acrolein is mainly produced by spermine oxidase in plasma. An increase in putrescine, spermine oxidase and acrolein in plasma was observed in all cases such as diabetic nephropathy, chronic glomerulonephritis and nephrosclerosis. After patients with chronic renal failure had undergone hemodialysis, their levels of plasma polyamines, spermine oxidase and acrolein returned towards normal. It is likely that acrolein produced from spermine accumulates in the blood due to decreased excretion into urine and may function as a uremic "toxin".
[Show abstract][Hide abstract] ABSTRACT: We found previously that plasma levels of acrolein (CH2=CHCHO) and spermine oxidase (SMO) were well correlated with the degree of severity of chronic renal failure. The aim of this study was to test whether the levels of these 2 markers and of acetylpolyamine oxidase (AcPAO) were increased in the plasma of stroke patients.
The activity of AcPAO and SMO and the level of protein-conjugated acrolein in plasma of the stroke patients and normal subjects were measured by high-performance liquid chromatography and ELISA, respectively. Focal infarcts were estimated by MRI or computed tomography (CT).
The levels of AcPAO, SMO, and acrolein were significantly increased in the plasma of stroke patients. The size of stroke was nearly parallel with the multiplied value of acrolein and total polyamine oxidase (AcPAO plus SMO). After the onset of stroke, an increase in AcPAO first occurred, followed by increased levels of SMO and finally acrolein. In 1 case, an increase in AcPAO and SMO preceded focal damage as detected by MRI or CT. Furthermore, stroke was confirmed by MRI in a number of mildly symptomatic patients (11 cases) who had increased levels of total polyamine oxidase and acrolein. Among apparently normal subjects (8 cases) who had high values of acroleinxtotal polyamine oxidase, stroke was found in 4 cases by MRI.
The results indicate that increased levels of AcPAO, SMO, and acrolein are good markers of stroke.
[Show abstract][Hide abstract] ABSTRACT: Nitric oxide (NO) is a potent regulator in the cardiovascular system; it is generated by the nitric oxide synthase (NOS) family of proteins. NO produced in endothelial cells plays a crucial role in vascular functions. The aim of this study was to clarify the effect of diabetes on aortic NO synthesis in a model of genetic hypertension and determine whether captopril modulates this effect. Diabetes was induced in ten weeks old spontaneously hypertensive rats (SHR) by streptozotocin injection. The rats were allocated into 3 groups: control group 1, non-diabetic SHR; group 2, diabetic SHR; group 3, diabetic SHR group receiving captopril at 80 mg/kg in drinking water for 4 weeks. Mean blood pressure (MBP) was measured once a week by tail-cuff method. Aortic NO metabolities (nitrite/nitrate) and endothelial NOS (NOS-3) were assayed by Griess reaction and by immunoblotting and immunohistochemistry, respectively. There was a significant decrease in nitrite/nitrate (NOx) in aortas of diabetic SHR compared with controls. The decrease of aortic NOx in diabetic SHR was accompanied by a decrease in NOS-3 expression. Captopril treatment reduced MBP without affecting either NOx level or NOS-3 expression in aortas of diabetic SHR. We conclude that STZ-induced diabetes decreased NO in aortas of SHR that may reflect endothelial cell dysfunction; captopril administration decreased MBP without affecting NO level in aortas of diabetic SHR which suggest that the blood pressure-lowering effects of captopril were independent of NO.
Life Sciences 08/2005; 77(9):1003-14. · 2.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In clinical studies, it has been difficult to evaluate the influence of haemodialysis (HD) parameters on HD clearance (CL(HD)) and reduction rate (RR) of non-ionic contrast medium during HD sessions. We therefore predicted clinical values of CL(HD) and RR of iopromide, a non-ionic contrast medium, from findings obtained from in vitro experiments, and confirmed that these predictive values were comparable with the actual values in clinical cases.
We developed a correlation equation for predicting CL(HD) on the basis of in vitro HD experiments by varying blood flow rates between 100 and 200 ml/min with a cuprammonium rayon dialyser (AM-SD-10H). Total body clearance of iopromide (CL(PT)) was estimated by the Cockroft-Gault equation. The volume of distribution (V(d)) was obtained from the reported value. By using the HD and three pharmacokinetic parameters (CL(HD), CL(PT) and V(d)), we predicted CL(HD) and RR for seven patients undergoing HD after the administration of iopromide.
In the in vitro study, the mean values (+/-SD) of iopromide clearance at blood flow rates of 100, 150 and 200 ml/min were 45.35 (2.54), 53.88 (6.46) and 57.61 (4.72) ml/min, respectively. There were highly significant correlations between clearance and blood flow rate (r = 0.975). Although the predicted CL(HD) showed a tendency towards underestimation, a good correlation was found. Predicted RR values were similar to observed values except for one case.
The in vitro model used in the present study provides pertinent information about CL(HD) and is helpful for predicting RR during HD in individual patients undergoing HD.
[Show abstract][Hide abstract] ABSTRACT: Background: Statins are associated with muscle complaints ranging from myalgia to rhabdomyolysis. We studied the genetic contribution to the risk of the statin-induced myopathy by comparing frequencies of mutant alleles of candidate genes in case and control groups.Methods: We studied ten Japanese patients with abnormal increase in plasma creatinine kinase or severe muscle complaints, in comparison with control patients (n=26) who received statins but had no myopathy. DNA samples were genotyped for 152 SNPs/mutations in eight candidate genes selected from genes responsible for inherited rhabdomyolysis and those involved in the metabolism or transport of stains.Results: No mutations or SNPs were detected in the genes of inherited rhabdomyolysis except for 128G>A in VLCAD, of which frequency was almost the same as that of the controls. For CYP3A4 and MRP2, one and two SNPs were detected respectively, but there was no significant difference between the groups. However, we found a significant association between OATP-C*15 and pravastatin- or atorvastatin-induced myopathy (P<0.01). An odds ratio of 11.3 (95%CI=1.6–80.3, P<0.05) was obtained when the possession of one or more OATP-C*15 was compared. In addition, an association between 2677G>A in MDR1 and simvastatin- or atorvastatin-incuced myopathy was also observed (P<0.05).Conclusions: The results suggest that OATP-C*15 is one of the susceptible factors for development of myopathy in patients taking pravastatin or atorvastatin.
[Show abstract][Hide abstract] ABSTRACT: Aristolochic acids (AA), present in Aristolochia plants, are the toxin responsible for Chinese herbs nephropathy (CHN), a rapidly progressive tubulointerstitial nephritis (TIN). To clarify the mechanisms of the development of CHN, we tried to induce TIN in mice using AA. Three strains of inbred mice, BALB/c, C3H/He and C57BL/6, received 2.5 mg kg(-1) of AA or AA sodium salt (AANa) daily by intraperitoneal or oral administration, 5 days a week for 2 weeks. Serum and renal tissue were obtained at sacrifice. Twelve-hour urine samples were individually collected in a metabolic cage at one-week intervals. In the AA-injected groups, severe tubular injury, with the appearance of acute tubular necrosis, and rare cell infiltration into the interstitium, were seen in BALB/c mice. C3H/He mice also developed TIN with prominent cell infiltration into the interstitium and interstitial fibrosis. In C57BL/6 mice, only mild and focal tubulointerstitial changes were seen. Serum creatinine and blood urea nitrogen increased in BALB/c and C3H/He mice. Immunofluorescent study revealed no deposition of immune components in kidneys. In the AANa-treated groups, TIN was also seen in all groups, but even more severe tubulointerstitial changes were induced by intraperitoneal injection. Further examination using purified AAI, AAII, AAIVa and aristolactam I (ALI) revealed that AAI induced strong nephrotoxicity in mice, and that AAII resulted in mild nephrotoxicity. However, AAIVa and ALI caused no nephrotoxicity in this experimental system. There are strain differences in mice in their susceptibility to AA nephropathy. AAI exerted the strongest nephrotoxic effect in mice.
Journal of Pharmacy and Pharmacology 03/2004; 56(2):221-9. · 2.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Semicarbazide-sensitive amine oxidase (SSAO, EC 126.96.36.199) is a group of enzymes highly sensitive to inhibition by semicarbazide. This high sensitivity distinguishes these enzymes from monoamine oxidase (MAO). Various mammalian tissues contain membrane-bound SSAO which metabolizes only the primary monoamines. Vascular and non-vascular smooth muscle cells have particularly high SSAO activity, but recently the enzyme activity has also been found in non-vascular smooth muscle cells. The substrate specificity of SSAO shows considerable species-related variations. A variety of compounds inhibiting MAO activity has also been identified as SSAO inhibitors. Among inhibitors, there is no specific SSAO inhibitor so far tested. Many studies reinforce the conclusion that inhibitory properties of some compounds against MAO activities has been markedly differed from their properties as SSAO inhibitors. 2-bromoethylamine has been recently developed with a potent, selective and suicide SSAO inhibitor without any inhibitory effect on MAO activity Using this inhibitor, it is possible to study the role of the enzyme in mammalian tissues. As physiological role the increased concentrations of SSAO, especially in blood plasma, have been found in diabetic patients and experimental animals. This enzyme was found to be associated with translocation of the glucose transporter GLUT 4 into the adipose cell surface and involved in the signaling of glucose uptake. Recent studies showed that vascular SSAO metabolizes endogenous primary amines, allylamine, methylamine and aminoacetone, to the corresponding cytotoxic aldehydes. These aldehydes have been linked to the ability of diabetic complications such as neuropathy, retinopathy and nephropathy. Overproduction of such toxic aldehydes produced by increased SSAO activity was proposed to be potentially hazardous in diabetic complications. Thus, reduction or inhibition of SSAO may be beneficial in these pathological conditions. Clearly species-related differences in properties of SSAO must be taken into account in this respect, particularly when assessing if SSAO inhibition may have great application in human.