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Carbon monoxide (CO) is a stress-inducible gas generated by heme oxygenase (HO) eliciting adaptive responses against toxicants; however, mechanisms for its reception remain unknown. Serendipitous observation in metabolome analysis in CO-overproducing livers suggested roles of cystathionine ␤-synthase (CBS) that rate-limits transsulfuration pathway and H 2 S generation, for the gas-responsive receptor. Studies using recombinant CBS indicated that CO binds to the prosthetic heme, stabilizing 6-coordinated CO-Fe(II)-histidine complex to block the activity, whereas nitric oxide (NO) forms 5-coordinated structure without inhibiting it. The CO-overproducing livers down-regulated H 2 S to stimulate HCO 3 ؊ -dependent choleresis: these responses were attenuated by blocking HO C arbon monoxide (CO) is generated from inducible heme oxygenase 1 (HO-1) and constitutive heme oxygenase 2 (HO-2), respectively, and has the ability to regulate neurovascular functions, 1,2 apoptotic responses, 3,4 and metabolism of xenobiotics and toxicants. 5,6 This gas is overproduced through increased delivery of heme as a substrate and the HO-1 induction on exposure to stressors such as hypoxia and oxidative stress. Mechanisms by which CO regulates cell functions appear to involve an activation of soluble guanylate cyclase (sGC), the enzyme that allows the gas to bind to the prosthetic heme to synthesize cyclic guanosine monophosphate as a second messenger. 1 Distinct from nitric oxide (NO) that forms 5-coordinated NO-Fe(II) complex to trigger full activation of the enzyme, CO activates this enzyme only modestly because the gas binding stabilizes 6-coordinated CO-Fe(II)-histidine complex. 7 Mitogen-activated protein kinase has also been shown to serve as a CO-responsive signal transducer. 8 Gene disruption of HO-1 increases sensitivity to overproduction of reactive oxygen species, inflammatory mediators or xenobiotic metabolism, whereas the gene transfer or CO inhalation under these circumstances suppresses such pathogenic responses. 7-9 However, direct mechanisms for the CO reception to trigger these adaptive responses of metabolism remain unknown.Because this gas has the ability to inhibit ferrous form of the prosthetic heme of enzymes, tryptophan 2,3-dioxygenase or cytochromes P450 have been considered puta-

Metabolome analyses assisted by capillary electrophoresis-mass spectrometry (CE-MS) have allowed us to systematically grasp changes in small molecular metabolites under disease conditions. We applied CE-MS to mine out biomarkers in hepatic ischemia-reperfusion. Rat livers were exposed to ischemia by clamping of the portal inlet followed by reperfusion. Metabolomic profiling revealed that l contents of taurine in liver and plasma were significantly increased. Of interest is an elevation of hypotaurine, collectively suggesting significance of hypotaurine/taurine in post-ischemic responses. Considering the anti-oxidative capacity of hypotaurine, we examined if supplementation of the compound or its precursor amino acids could affect hepatocellular viability and contents of taurine in liver and plasma. Administration of hypotaurine, N-acetylcysteine or methionine upon reperfusion comparablly attenuated the post-ischemic hepatocellular injury but with different metabolomic profiling among groups: rats treated with methionine or N-acetylcysteine but not those treated with hypotaurine, exhibited significant elevation of hepatic lactate generation without notable recovery of the energy charge. Furthermore, the group treated with hypotaurine exhibited elevation of the plasma taurine, suggesting that the exogenously administered compound was utilized as an antioxidant. These results suggest that taurine serves as a surrogate marker for ischemia-reperfusion indicating effectiveness of hypotaurine as an energy-saving hepatoprotective amino acid.

Cystathionine gamma-lyase (CSE) is an enzyme catalyzing cystathionine and cysteine to yield cysteine and hydrogen sulfide (H(2)S), respectively. This study aimed to examine if H(2)S generated from the enzyme could serve as an endogenous regulator of hepatobiliary function. Gas chromatographic analyses indicated that, among rat organs herein examined, liver constituted one of the greatest components of H(2)S generation in the body, at 100 mumol/g of tissue, comparable to that in kidney and 1.5-fold greater than that in brain, where roles of the gas in the regulation of neurotransmission were reported previously. At least half of the gas amount in the liver appeared to be derived from CSE, because blockade of the enzyme by propargylglycine suppressed it by 50%. Immunohistochemistry revealed that CSE occurs not only in hepatocytes, but also in bile duct. In livers in vivo, as well as in those perfused ex vivo, treatment with the CSE inhibitor induced choleresis by stimulating the basal excretion of bicarbonate in bile samples. Transportal supplementation of NaHS at 30 mumol/L, but not that of N-acetylcysteine as a cysteine donor, abolished these changes elicited by the CSE inhibitor in the perfused liver. The changes elicited by the CSE blockade did not coincide with alterations in hepatic vascular resistance, showing little involvement of vasodilatory effects of the gas in these events, if any. These results first provided evidence that H(2)S generated through CSE modulates biliary bicarbonate excretion and is thus a determinant of bile salt-independent bile formation in the rat liver.

Background: Although surgery is the definitive curative treatment for biliary tract cancer (BTC), outcomes after surgery alone have not been satisfactory. Adjuvant therapy with S-1 may improve survival in patients with BTC. This study examined the safety and efficacy of 1 year adjuvant S-1 therapy for BTC in a multi-institutional trial. Methods: The inclusion criteria were as follows: histologically proven BTC, Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, R0 or R1 surgery performed, cancer classified as Stage IB to III. Within 10 weeks post-surgery, a 42-day cycle of treatment with S-1 (80 mg/m 2 /day orally twice daily on days 1-28 of each cycle) was initiated and continued up to 1 year post surgery. The primary endpoint was adjuvant therapy completion rate. The secondary endpoints were toxicities, disease-free survival (DFS), and overall survival (OS). Results: Forty-six patients met the inclusion criteria of whom 19 had extrahepatic cholangiocarcinoma, 10 had gallbladder carcinoma, 9 had ampullary carcinoma, and 8 had intrahepatic cholangiocarcinoma. Overall, 25 patients completed adjuvant chemotherapy, with a 54.3% completion rate while the completion rate without recurrence during the 1 year administration was 62.5%. Seven patients (15%) experienced adverse events (grade 3/4). The median number of courses administered was 7.5. Thirteen patients needed dose reduction or temporary therapy withdrawal. OS and DFS rates at 1/2 years were 91.2/80.0% and 84.3/77.2%, respectively. Among patients who were administered more than 3 courses of S-1, only one patient discontinued because of adverse events.

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Choledochal cyst (CC)—a congenital anomaly of the bile duct—is rare. We report a 28-year-old woman complaining of epigastralgia who was transferred to our hospital. Physical examination revealed severe tenderness to abdominal palpation without symptoms of diffuse peritonitis. Urgent contrast-enhanced abdominal computed tomography indicated the dilated common bile duct (CBD) was perforated, with a presumed diagnosis of perforated CC. Endoscopic external biliary drainage was performed immediately as a bridging procedure to the definitive surgery. Additional evaluations confirmed a type IVa CC, according to Todani’s classification, but no signs of malignancy. Twenty-two days after biliary drainage, laparotomy was performed. A large cystic mass was found in the CBD with a perforated scar on the right-side wall. Because inflammation around the pancreas head was too severe to perform cyst excision safely, the patient underwent subtotal stomach-preserving pancreatoduodenectomy. The postoperative course was uneventful, and the patient was discharged on the 29th postoperative day. Pathologic examination of a specimen showed no malignancy, and the patient has remained well during the 3-year follow-up. Our experience with this case suggests that definitive single-stage surgery for perforated CC in an adult can be performed safely owing to external biliary drainage as a bridging procedure, if manifestation of diffuse peritonitis is not evident.