Background/Aims: To clarify the mechanism of persistent cholestasis after massive hepatectomy, the relationship between such cholestasis and the expression and localization of organic anion transporters for bile acids was examined in a rat model. Methods: Male Sprague-Dawley rats were subjected to 90% hepatectomy, and tissues were harvested on 0, 1, 3, and 7 days for microarray analysis, the quantitative real-time polymerase chain reaction （RT-PCR） , Western blotting and immunohistochemistry to examine the expression of multidrug resistance protein 4 （Mrp4） , bile salt export pump （Bsep） and sodium-dependent taurocholate cotransporting polypeptide （Ntcp） . Results: Persistently elevated serum bile acids were observed on days 3 and 7. RT-PCR and Western blotting indicated that the expression of Mrp4, a bile acid export pump located in the basolateral membrane, was increased on day 3. Ntcp, a transporter used to uptake bile acids from the sinusoids, was significantly decreased throughout the period. Bsep, an export pump localized to the canalicular membrane, was unchanged. Immunohistochemistry revealed the localization of Mrp4 and Bsep in the basolateral and canalicular membranes, respectively. On the other hand, Ntcp was localized in the cytoplasm on days 3 and 7 and was hardly detected in the basolateral membrane. Conclusions: These results suggested that the sustained repression and translocation of Ntcp and the expression of Mrp4 at the basolateral membrane seemed to be responsible for the high blood bile acids levels after massive hepatectomy.Hirosaki Med．J. 64, Supplement：S99-S106，2013

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Peroxisome proliferators (PP), including clofibrate (CF), are nongenotoxic rodent carcinogens, and oxidative DNA damages are suggested as a causative event for carcinogenesis. Gene expression profiles differ between hepatic lesions induced by PP and genotoxic carcinogens. Our previous study revealed that expression of L-bifunctional enzyme (enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase, BE) was repressed in preneoplastic lesions induced by PP, whereas it was enhanced in the surrounding tissues. In the present study, we immunohistochemically examined expression of the specific glutathione S-transferase (GST) form, GST-A4, which detoxifies 4-hydroxy-alkenal, the end-product of lipid peroxides, and nuclear factor-erythroid 2-related factor 2 (Nrf2), a transcription factor for many genes encoding drug-metabolizing enzymes and defending enzymes against oxidative stress, during rat hepatocarcinogenesis induced by CF and genotoxic carcinogens. GST-A4 and Nrf2 were not expressed in BE-negative foci at 8 weeks of CF administration, but were expressed in the foci at 60 weeks. GST-A4-positive foci appeared at later stages than BEnegative foci, but its localization was coincidental with that of the latter foci. The areas of GST-A4-positive foci were larger than those of BE-negative foci without GST-A4 expression. Most GST-A4-positive foci were also positive for Nrf2. In rat livers induced by genotoxic carcinogens, GST-P-negative foci as well as GST-P-positive foci were demonstrated. GST-A4 and Nrf2 were expressed in GST-P-negative foci, whereas they were not expressed in most GST-P-positive foci. Thus, GST-A4-positive foci developed in rat livers by CF and genotoxic carcinogen administration, indicating that the enzyme is a positive marker for hepatic foci induced by these different carcinogens. (Cancer Sci 2010; 101: 1093-1098 P eroxisome proliferators (PP), including clofibrate (CF), induce hepatomegaly, proliferation of peroxisomes, and expression of several peroxisomal enzymes in rodent livers, such as acyl-CoA oxidase and L-bifunctional enzyme (BE), which participate in the b-oxidation of fatty acids and result in the production of hydrogen peroxide.(1-3) Prolonged administration of PP to rats is associated with the development of hepatic preneoplastic and neoplastic lesions.(4,5) As PP do not cause mutagenic effects in short-term in vitro assays, (6,7) administration of PP to rats for 60-100 weeks is required to evaluate their carcinogenic potential. PP include a broad spectrum of compounds of industrial, pharmaceutical, and agricultural importance, such as phthalate ester plasticizers, lipid-lowering drugs, and herbicides.(8) Thus, methods for early detection of the carcinogenic potential of PP are required. PP are non-genotoxic rodent carcinogens and their carcinogenic processes are suggested to differ from the processes of genotoxic carcinogens. (6,7) Gene expression profiles differ between hepatic lesions induced by PP and those by genotoxic agents.(9,10) The former lesions do not express GST-P, (11) a relia...

Purpose: We investigated the clinical value of mechanical and chemical bowel preparations (MBP, CBP) for preventing surgical site infection (SSI) in patients undergoing elective laparoscopic colorectal surgery. Methods: This retrospective cohort study included 475 patients who underwent elective laparoscopic colorectal surgery between January 2018 and March 2022. CBP was introduced in January 2021. CBP included kanamycin (1 g) and metronidazole (1 g) two times a day, the day before surgery. In some cases, MBP was omitted in patients who planned to undergo right-sided colectomy, those with tumor obstruction, and those with poor general condition, depending on the physician’s judgment. The endpoints were primarily the overall incidence of SSI, and secondarily incisional SSI, organ-space SSI, culture from the surgical site, and postoperative hospital stay. Results: In total, 136 patients underwent CBP. MBP was omitted in 53 patients. Overall, SSI occurred in 80 patients (16.8%), including 61 cases of incisional SSI (12.8%) and 36 cases of organ-space SSI (7.6%). Multivariate logistic regression revealed that CBP exerted an independent preventive effect on overall and incisional SSI, whereas MBP did not. Levels of Bacteroides species at the surgical site were significantly lower in the CBP group than in the non-CBP group. Postoperative hospital stay was significantly longer in the incisional SSI group than in non-SSI group and was significantly longer in the organ-space SSI group than in the other groups.Conclusion: CBP, but not MBP, exerts an independent preventive effect on SSI, especially incisional SSI, in patients undergoing elective laparoscopic colorectal surgery.

Peroxisome proliferators (PPs), non-genotoxic rodent carcinogens, cause the induction of the peroxisomal fatty acid b-oxidation system, including bifunctional enzyme (BE) and 3-ketoacyl-CoA thiolase (TH), in the liver. GST M1 gene is polymorphic in SpragueDawley rats, NC-and KS-type. The KS-type rats showed enhanced susceptibility to ethyl-a-chlorophenoxyisobutyrate (clofibrate, CF), one of the PPs. The degree of BE induction was higher in the KStype and preneoplastic foci developed after 6-8 weeks of treatment, whereas no foci developed in the NC-type. In the preset study, factors involved in different BE inducibility were investigated. There were no differences in hepatic peroxisome proliferator-activated receptor (PPAR) a levels between them. Among various coactivators for PPARa, only steroid receptor coactivator (SRC)-3 level was higher in the KS-type. To investigate the association between PPARa and SRC-3 or other proteins, nuclear extracts from CF-treated livers were applied to a PPARa column. In the KStype, 110, 72, and 42 kDa proteins were bound and these were identified as SRC-3, BE, and TH, respectively. EMSA supported the binding of these proteins to PPARa associated to the BE enhancer in CF-treated KS-type, but not in the NC-type. Histone H3 acetylation was increased 11-fold in the KS-type by CF treatment but not in the NC-type. As BE and TH are responsible for acetyl-CoA production and SRC-3 possesses a histone acetyltransferase activity, these results suggest that enhanced BE induction in the KS-type livers is due to acetylation-mediated transcriptional activation and epigenetic mechanisms might be involved in CF-induced rat hepatocarcinogenesis. (Cancer Sci 2010; 101: 869-875) E thyl-a-chlorophenoxyisobutyrate, a hypolipidemic agent, and other PPs, when given to rats and mice results in a marked increase in the number and size of peroxisomes and increase in liver weight. These chemicals also induce the peroxisomal fatty acid b-oxidation enzyme system in the liver, (1)(2)(3) composed of three proteins.(4,5) The first, acyl-CoA oxidase, catalyzes dehydrogenation of fatty acyl-CoA, leading to the production of enoyl-CoA and H 2 O 2 . The second, BE, catalyzes the production of 3-ketoacyl-CoA from enoyl-CoA. The third, TH, is involved in the formation of acetyl-CoA. (4,5) In addition, when given long term, PPs result in the formation of rodent hepatic preneoplastic lesions and hepatocellular carcinomas. (6,7) Glutathione transferases are a group of multifunctional enzymes that catalyse the conjugation of many electrophiles with glutathione. They have been classified into several groups, alpha, mu, pi, theta, sigma, and zeta.(8) Hepatic GSTs are involved in detoxication and conjugation reactions, and GST M1-1, M1-2, and M2-2, the major forms of rat liver GSTs in the mu class, are activated by reactive oxygen species.(9) The GST M1 gene is polymorphic in Sprague-Dawley rats, one type encoding 198 Cys (NC-type), and another encoding 198 Ser (KS-type). (10,11) In our previous study, the KStype rats s...