As shown in Fig 1 (right panel), the condensation between taxifo

As shown in Fig. 1 (right panel), the condensation between taxifolin and coniferyl alcohol has two possible outcomes, thereby

generating two different molecules that differ based on the position of the primary alcohol, which can either extend out of the page, or face into the page. Thus, silybin B has the alcohol protruding from the page and the benzene ring faces into the page, while silybin A has the opposite configuration. Since there are two different stereocenters that differ between silybin A and silybin B, they are called diastereoisomers. Since there is inconsistency in the literature with respect to naming silymarin-derived compounds, we adopt the recommendations of Kroll et al.19: Silymarin is the entire extract containing seven flavonolignans and taxifolin. Silibinin is a mixture of silybin A and silybin B in a 1:1 ratio. The remaining flavonolignans GSK3235025 molecular weight are: isosilybin A, isosilybin B, silychristin, isosilychristin, and silydianin. The flavonoid found in silymarin is taxifolin. The structures of the eight compounds are shown in Fig. 2. In a typical preparation of silymarin, the approximate percentages of the eight major components DZNeP ic50 are silybin A (16%), silybin B (24%), isosilybin A (6%), isosilybin B (4%), silydianin (16%), silychristin (12%), isosilychristin

(2%), and taxifolin (2%).20 The product composition totals are less than 100% because a typical extract is usually labeled as 70% to 80% silymarin, with the remainder consisting of uncharacterized medchemexpress polyphenols and aliphatic fatty acids such

as oleic and palmitic acids. Silymarin is fat soluble, with an oral bioavailability of 30%-50%. In healthy subjects, oral dosing of silymarin results in low plasma concentrations of flavonolignans between 50-300 ng/mL because the parent compounds are rapidly metabolized to glucuronide and sulfate conjugates which are not thought to have biological activity.21-25 Plasma levels typically achieve maximum concentration after ∼1-2 hours, with an estimated half-life of 4-6 hours.21, 24, 25 Approximately 20%-40% is conjugated and excreted in the bile, 3%-8% excreted in the urine, and the remainder excreted unabsorbed in the feces.26 In cirrhosis patients, the peak serum concentration and time to peak concentration are delayed, suggesting that impaired biliary excretion may be associated with reduced clearance of conjugated silibinin.26 This has also been observed for cirrhosis patients with chronic HCV, who have 3- to 5-fold higher plasma concentrations of flavonolignan conjugates as compared to healthy subjects.6, 27, 28 Silymarin may induce cytochrome P450, isoform 3A429 and p-glycoprotein,30 which may alter the pharmacokinetics of oral contraceptive pills. Metabolism of other drugs may also be affected, including antihistamines, benzodiazepines, protease-inhibitors, and cholesterol-lowering agents.

As shown in Fig 1 (right panel), the condensation between taxifo

As shown in Fig. 1 (right panel), the condensation between taxifolin and coniferyl alcohol has two possible outcomes, thereby

generating two different molecules that differ based on the position of the primary alcohol, which can either extend out of the page, or face into the page. Thus, silybin B has the alcohol protruding from the page and the benzene ring faces into the page, while silybin A has the opposite configuration. Since there are two different stereocenters that differ between silybin A and silybin B, they are called diastereoisomers. Since there is inconsistency in the literature with respect to naming silymarin-derived compounds, we adopt the recommendations of Kroll et al.19: Silymarin is the entire extract containing seven flavonolignans and taxifolin. Silibinin is a mixture of silybin A and silybin B in a 1:1 ratio. The remaining flavonolignans Pexidartinib are: isosilybin A, isosilybin B, silychristin, isosilychristin, and silydianin. The flavonoid found in silymarin is taxifolin. The structures of the eight compounds are shown in Fig. 2. In a typical preparation of silymarin, the approximate percentages of the eight major components this website are silybin A (16%), silybin B (24%), isosilybin A (6%), isosilybin B (4%), silydianin (16%), silychristin (12%), isosilychristin

(2%), and taxifolin (2%).20 The product composition totals are less than 100% because a typical extract is usually labeled as 70% to 80% silymarin, with the remainder consisting of uncharacterized MCE polyphenols and aliphatic fatty acids such

as oleic and palmitic acids. Silymarin is fat soluble, with an oral bioavailability of 30%-50%. In healthy subjects, oral dosing of silymarin results in low plasma concentrations of flavonolignans between 50-300 ng/mL because the parent compounds are rapidly metabolized to glucuronide and sulfate conjugates which are not thought to have biological activity.21-25 Plasma levels typically achieve maximum concentration after ∼1-2 hours, with an estimated half-life of 4-6 hours.21, 24, 25 Approximately 20%-40% is conjugated and excreted in the bile, 3%-8% excreted in the urine, and the remainder excreted unabsorbed in the feces.26 In cirrhosis patients, the peak serum concentration and time to peak concentration are delayed, suggesting that impaired biliary excretion may be associated with reduced clearance of conjugated silibinin.26 This has also been observed for cirrhosis patients with chronic HCV, who have 3- to 5-fold higher plasma concentrations of flavonolignan conjugates as compared to healthy subjects.6, 27, 28 Silymarin may induce cytochrome P450, isoform 3A429 and p-glycoprotein,30 which may alter the pharmacokinetics of oral contraceptive pills. Metabolism of other drugs may also be affected, including antihistamines, benzodiazepines, protease-inhibitors, and cholesterol-lowering agents.

As shown in Fig 1 (right panel), the condensation between taxifo

As shown in Fig. 1 (right panel), the condensation between taxifolin and coniferyl alcohol has two possible outcomes, thereby

generating two different molecules that differ based on the position of the primary alcohol, which can either extend out of the page, or face into the page. Thus, silybin B has the alcohol protruding from the page and the benzene ring faces into the page, while silybin A has the opposite configuration. Since there are two different stereocenters that differ between silybin A and silybin B, they are called diastereoisomers. Since there is inconsistency in the literature with respect to naming silymarin-derived compounds, we adopt the recommendations of Kroll et al.19: Silymarin is the entire extract containing seven flavonolignans and taxifolin. Silibinin is a mixture of silybin A and silybin B in a 1:1 ratio. The remaining flavonolignans LY2157299 mouse are: isosilybin A, isosilybin B, silychristin, isosilychristin, and silydianin. The flavonoid found in silymarin is taxifolin. The structures of the eight compounds are shown in Fig. 2. In a typical preparation of silymarin, the approximate percentages of the eight major components Alvelestat ic50 are silybin A (16%), silybin B (24%), isosilybin A (6%), isosilybin B (4%), silydianin (16%), silychristin (12%), isosilychristin

(2%), and taxifolin (2%).20 The product composition totals are less than 100% because a typical extract is usually labeled as 70% to 80% silymarin, with the remainder consisting of uncharacterized medchemexpress polyphenols and aliphatic fatty acids such

as oleic and palmitic acids. Silymarin is fat soluble, with an oral bioavailability of 30%-50%. In healthy subjects, oral dosing of silymarin results in low plasma concentrations of flavonolignans between 50-300 ng/mL because the parent compounds are rapidly metabolized to glucuronide and sulfate conjugates which are not thought to have biological activity.21-25 Plasma levels typically achieve maximum concentration after ∼1-2 hours, with an estimated half-life of 4-6 hours.21, 24, 25 Approximately 20%-40% is conjugated and excreted in the bile, 3%-8% excreted in the urine, and the remainder excreted unabsorbed in the feces.26 In cirrhosis patients, the peak serum concentration and time to peak concentration are delayed, suggesting that impaired biliary excretion may be associated with reduced clearance of conjugated silibinin.26 This has also been observed for cirrhosis patients with chronic HCV, who have 3- to 5-fold higher plasma concentrations of flavonolignan conjugates as compared to healthy subjects.6, 27, 28 Silymarin may induce cytochrome P450, isoform 3A429 and p-glycoprotein,30 which may alter the pharmacokinetics of oral contraceptive pills. Metabolism of other drugs may also be affected, including antihistamines, benzodiazepines, protease-inhibitors, and cholesterol-lowering agents.

This was followed during the next 15 years by Standards for sever

This was followed during the next 15 years by Standards for several other hormones and for antibiotics and antitoxins. Internationally the work was organized initially under the auspices

of the League of Nations, via an ad hoc Committee, but the main protagonists were NIMR and the State Serum Institute in Copenhagen. In 1947 the newly established World Health Organisation (WHO) established an Expert Committee on Biological Standardisation, which took over all responsibilities in this area. Further details of the history of biological standardization are given in a book by Derek Bangham [11]. The first Standard in the area of haemostasis and thrombosis was the IS for heparin, established in 1942 [12]. In the 1960s Wnt assay work commenced on establishing Reference Preparations for thromboplastin reagents, because of their widespread use in control of oral anticoagulation; these would eventually be established in the 1970s by WHO as International Reference Preparations [13].

In the meantime, work had also begun towards preparations of an IS for one of the clotting factors, FVIII. The need for a standard for FVIII was increasingly recognized during the 1960s as treatment with, first cryoprecipitate, then intermediate purity concentrates started to take hold – it became particularly important when concentrates were manufactured and sold commercially around the world, and were priced by the unit. Although cryoprecipitate was widely used as therapy in the 1960s it was considered unsuitable as a standard because of possible medchemexpress difficulties in freeze drying and uncertain stability. The two materials studied were a normal plasma pool, supplied by the Oxford Transfusion Centre, Selumetinib and an intermediate purity concentrate, supplied by Dr Alan Johnson of New York. These two materials were ampouled at NIMR and sent out to 20 expert laboratories around the world; each laboratory assayed these samples against their own local standard, which was usually a plasma pool from local donors (i.e. laboratory staff), though in one case was a plasma sample from a single individual, the clinical haematologist himself! This was the first

time that FVIII assays in different labs had been compared on the same samples, and the results were a surprise to many experts in the field. The potency of the concentrate estimated by the various labs covered a 10-fold range! The variability on the plasma sample was considerably less, though still high. This is a graphic illustration of the importance of ‘like vs. like’, and it might be thought that the high variability in assays of the concentrate would mitigate against its use as a standard. However, bearing in mind the increasing use and availability of FVIII concentrates, it was thought preferable to establish a concentrate standard, on the basis of ‘like vs. like’; the concentrate was also more stable than the plasma. The concentrate was duly established as the first IS for FVIII by WHO in 1970 [14].

This was followed during the next 15 years by Standards for sever

This was followed during the next 15 years by Standards for several other hormones and for antibiotics and antitoxins. Internationally the work was organized initially under the auspices

of the League of Nations, via an ad hoc Committee, but the main protagonists were NIMR and the State Serum Institute in Copenhagen. In 1947 the newly established World Health Organisation (WHO) established an Expert Committee on Biological Standardisation, which took over all responsibilities in this area. Further details of the history of biological standardization are given in a book by Derek Bangham [11]. The first Standard in the area of haemostasis and thrombosis was the IS for heparin, established in 1942 [12]. In the 1960s Protein Tyrosine Kinase inhibitor work commenced on establishing Reference Preparations for thromboplastin reagents, because of their widespread use in control of oral anticoagulation; these would eventually be established in the 1970s by WHO as International Reference Preparations [13].

In the meantime, work had also begun towards preparations of an IS for one of the clotting factors, FVIII. The need for a standard for FVIII was increasingly recognized during the 1960s as treatment with, first cryoprecipitate, then intermediate purity concentrates started to take hold – it became particularly important when concentrates were manufactured and sold commercially around the world, and were priced by the unit. Although cryoprecipitate was widely used as therapy in the 1960s it was considered unsuitable as a standard because of possible MCE difficulties in freeze drying and uncertain stability. The two materials studied were a normal plasma pool, supplied by the Oxford Transfusion Centre, Temozolomide and an intermediate purity concentrate, supplied by Dr Alan Johnson of New York. These two materials were ampouled at NIMR and sent out to 20 expert laboratories around the world; each laboratory assayed these samples against their own local standard, which was usually a plasma pool from local donors (i.e. laboratory staff), though in one case was a plasma sample from a single individual, the clinical haematologist himself! This was the first

time that FVIII assays in different labs had been compared on the same samples, and the results were a surprise to many experts in the field. The potency of the concentrate estimated by the various labs covered a 10-fold range! The variability on the plasma sample was considerably less, though still high. This is a graphic illustration of the importance of ‘like vs. like’, and it might be thought that the high variability in assays of the concentrate would mitigate against its use as a standard. However, bearing in mind the increasing use and availability of FVIII concentrates, it was thought preferable to establish a concentrate standard, on the basis of ‘like vs. like’; the concentrate was also more stable than the plasma. The concentrate was duly established as the first IS for FVIII by WHO in 1970 [14].

We hypothesize that biliary HCO secretion in humans serves to mai

We hypothesize that biliary HCO secretion in humans serves to maintain an alkaline pH near the apical surface of hepatocytes and cholangiocytes to

prevent the uncontrolled membrane permeation of protonated glycine-conjugated bile acids. Functional impairment of biliary HCO formation or its regulation may lead to enhanced vulnerability of cholangiocytes beta-catenin inhibitor and periportal hepatocytes toward the attack of hydrophobic bile acids. An interplay of hepatocellular and cholangiocellular ATP secretion, ATP/P2Y- and bile salt/TGR5-mediated Cl−/ HCO exchange and HCO secretion, and alkaline phosphatase-mediated ATP breakdown may guarantee a stable HCO umbrella under physiological conditions. Our hypothesis offers an attractive mechanistic link between AE2 deficiency/functional impairment in PBC patients5-8, 63 and development of fibrosing cholangitis of interlobular bile ductules in these patients. Impaired biliary HCO formation as in PBC would render small ductules ITF2357 datasheet most vulnerable for bile acid–induced cell damage, because they do not express mucins. Thus, immunological

alterations in PBC could be the consequence rather than the cause of bile acid–induced cholangiocyte damage in PBC as proposed.2 A defective biliary HCO umbrella could furthermore contribute to explain the heretofore enigmatic pathogenesis of various other fibrosing cholangiopathies. Genome screening of patients with PSC has disclosed GPBAR-1/TGR5 as a susceptibility gene10 that, when defective, may affect the biliary HCO umbrella. TGR5 is expressed on cilia of intrahepatic and extrahepatic bile ducts,

the site where bile duct alterations in PSC are observed. Cystic fibrosis–associated liver disease due to CFTR deficiency 上海皓元 and sclerosing cholangitis/nonanastomotic bile duct stricturing in the posttransplantation setting after vagal denervation both involve potential impairment of HCO formation. The vulnerability of the denervated biliary tree in the liver graft after transplantation may in part originate from a not yet fully developed arterial circulation around the bile ducts and the associated difficulty to maintain an alkaline pH at the apical surface of cholangiocytes. The same mechanism of defective biliary HCO secretion may even hold for the biliary cast syndrome after ischemic or septic bile duct injury in the intensive care setting28 when acute hypoxia in the biliary plexus may lead to disruption of the biliary HCO umbrella, and subsequently to cholangiocyte damage due to the unhindered actions of protonated glycine-conjugated bile acids.

We hypothesize that biliary HCO secretion in humans serves to mai

We hypothesize that biliary HCO secretion in humans serves to maintain an alkaline pH near the apical surface of hepatocytes and cholangiocytes to

prevent the uncontrolled membrane permeation of protonated glycine-conjugated bile acids. Functional impairment of biliary HCO formation or its regulation may lead to enhanced vulnerability of cholangiocytes selleck inhibitor and periportal hepatocytes toward the attack of hydrophobic bile acids. An interplay of hepatocellular and cholangiocellular ATP secretion, ATP/P2Y- and bile salt/TGR5-mediated Cl−/ HCO exchange and HCO secretion, and alkaline phosphatase-mediated ATP breakdown may guarantee a stable HCO umbrella under physiological conditions. Our hypothesis offers an attractive mechanistic link between AE2 deficiency/functional impairment in PBC patients5-8, 63 and development of fibrosing cholangitis of interlobular bile ductules in these patients. Impaired biliary HCO formation as in PBC would render small ductules ABT-263 cell line most vulnerable for bile acid–induced cell damage, because they do not express mucins. Thus, immunological

alterations in PBC could be the consequence rather than the cause of bile acid–induced cholangiocyte damage in PBC as proposed.2 A defective biliary HCO umbrella could furthermore contribute to explain the heretofore enigmatic pathogenesis of various other fibrosing cholangiopathies. Genome screening of patients with PSC has disclosed GPBAR-1/TGR5 as a susceptibility gene10 that, when defective, may affect the biliary HCO umbrella. TGR5 is expressed on cilia of intrahepatic and extrahepatic bile ducts,

the site where bile duct alterations in PSC are observed. Cystic fibrosis–associated liver disease due to CFTR deficiency MCE and sclerosing cholangitis/nonanastomotic bile duct stricturing in the posttransplantation setting after vagal denervation both involve potential impairment of HCO formation. The vulnerability of the denervated biliary tree in the liver graft after transplantation may in part originate from a not yet fully developed arterial circulation around the bile ducts and the associated difficulty to maintain an alkaline pH at the apical surface of cholangiocytes. The same mechanism of defective biliary HCO secretion may even hold for the biliary cast syndrome after ischemic or septic bile duct injury in the intensive care setting28 when acute hypoxia in the biliary plexus may lead to disruption of the biliary HCO umbrella, and subsequently to cholangiocyte damage due to the unhindered actions of protonated glycine-conjugated bile acids.

We hypothesize that biliary HCO secretion in humans serves to mai

We hypothesize that biliary HCO secretion in humans serves to maintain an alkaline pH near the apical surface of hepatocytes and cholangiocytes to

prevent the uncontrolled membrane permeation of protonated glycine-conjugated bile acids. Functional impairment of biliary HCO formation or its regulation may lead to enhanced vulnerability of cholangiocytes find more and periportal hepatocytes toward the attack of hydrophobic bile acids. An interplay of hepatocellular and cholangiocellular ATP secretion, ATP/P2Y- and bile salt/TGR5-mediated Cl−/ HCO exchange and HCO secretion, and alkaline phosphatase-mediated ATP breakdown may guarantee a stable HCO umbrella under physiological conditions. Our hypothesis offers an attractive mechanistic link between AE2 deficiency/functional impairment in PBC patients5-8, 63 and development of fibrosing cholangitis of interlobular bile ductules in these patients. Impaired biliary HCO formation as in PBC would render small ductules click here most vulnerable for bile acid–induced cell damage, because they do not express mucins. Thus, immunological

alterations in PBC could be the consequence rather than the cause of bile acid–induced cholangiocyte damage in PBC as proposed.2 A defective biliary HCO umbrella could furthermore contribute to explain the heretofore enigmatic pathogenesis of various other fibrosing cholangiopathies. Genome screening of patients with PSC has disclosed GPBAR-1/TGR5 as a susceptibility gene10 that, when defective, may affect the biliary HCO umbrella. TGR5 is expressed on cilia of intrahepatic and extrahepatic bile ducts,

the site where bile duct alterations in PSC are observed. Cystic fibrosis–associated liver disease due to CFTR deficiency 上海皓元医药股份有限公司 and sclerosing cholangitis/nonanastomotic bile duct stricturing in the posttransplantation setting after vagal denervation both involve potential impairment of HCO formation. The vulnerability of the denervated biliary tree in the liver graft after transplantation may in part originate from a not yet fully developed arterial circulation around the bile ducts and the associated difficulty to maintain an alkaline pH at the apical surface of cholangiocytes. The same mechanism of defective biliary HCO secretion may even hold for the biliary cast syndrome after ischemic or septic bile duct injury in the intensive care setting28 when acute hypoxia in the biliary plexus may lead to disruption of the biliary HCO umbrella, and subsequently to cholangiocyte damage due to the unhindered actions of protonated glycine-conjugated bile acids.

6 mL CCl4/kg body weight; thrice weekly for 4 weeks; n = 3 mice p

6 mL CCl4/kg body weight; thrice weekly for 4 weeks; n = 3 mice per group), a three-dimensional high-resolution inversion recovery gradient echo delayed-enhancement MRI (DE-MRI; see Makowski et see more al.[4] for details on MR parameters and methodology) of liver tissue indicated clear differences between normal and diseased animals

(Fig. 1): while healthy livers displayed no focal contrast enhancement upon ESMA administration (Fig. 1D,E), very distinct perivascular signals were observed in large and medium-sized vessels in fibrotic livers (Fig. 1A,B). This observation was in line with periportal ECM deposition visualized using Elastica-Van-Gieson staining (Fig. 1C,F). Although these findings require further investigation (with

regard to fibrosis stage, ESMA dose, timing, specificity, and quantification), they demonstrate that elastin-based molecular MRI, like collagen-based molecular MRI,[3] may be suitable for noninvasive monitoring of ECM remodeling during liver fibrosis. As the collagen-to-elastin-ratio changes during the progression and regression of liver fibrosis,[2] the selective or combined use of different molecular MR probes might be a promising strategy for translating the differential regulation of ECM proteins during fibrosis pro- and regression into novel noninvasive imaging techniques for the clinic. Supported by the German Research Foundation (DFG SFB/TRR57; TA434/2-1; AZD5363 price EH412/1-1; LA2937/1-1) and British Heart Foundation (RG/12/1/29262). ESMA was kindly provided by David Onthank (Lantheus Medical Imaging, North Billerica, MA). “
“The mechanism of idiosyncratic drug-induced liver injury (IDILI) remains poorly understood, to a large degree because of the lack of a valid animal model. Recently, we reported an animal model in which treatment of female C57BL/6 mice with amodiaquine (AQ) resulted in mild liver injury with a delayed onset and resolution despite continued treatment. Such adaptation is a common 上海皓元 outcome in the IDILI caused by drugs that can cause liver failure. We had hypothesized that most IDILI is immune mediated and adaptation represents immune tolerance. In this study

we found that AQ treatment of Cbl-b-/- and PD-1-/- mice, which have impaired immune tolerance, resulted in a slightly greater injury. Co-treatment of C57BL/6 with AQ and anti-CTLA4 also resulted in a greater increase in ALT than treatment with AQ alone; however, these mice also had an increase in Treg cells, and T helper cells expressing PD-1 and CTLA4. The increase in these cells implies the induction of immune tolerance, and the ALT activity in these mice returned to normal despite continued treatment. Co-treatment of PD-1-/- mice with anti-CTLA4 antibody and AQ resulted in the greatest increase in ALT (200 – 300 U/L), and necroinflammatory responses characterized by portal infiltration of lymphocytes with interface hepatitis.

6 mL CCl4/kg body weight; thrice weekly for 4 weeks; n = 3 mice p

6 mL CCl4/kg body weight; thrice weekly for 4 weeks; n = 3 mice per group), a three-dimensional high-resolution inversion recovery gradient echo delayed-enhancement MRI (DE-MRI; see Makowski et KU-57788 order al.[4] for details on MR parameters and methodology) of liver tissue indicated clear differences between normal and diseased animals

(Fig. 1): while healthy livers displayed no focal contrast enhancement upon ESMA administration (Fig. 1D,E), very distinct perivascular signals were observed in large and medium-sized vessels in fibrotic livers (Fig. 1A,B). This observation was in line with periportal ECM deposition visualized using Elastica-Van-Gieson staining (Fig. 1C,F). Although these findings require further investigation (with

regard to fibrosis stage, ESMA dose, timing, specificity, and quantification), they demonstrate that elastin-based molecular MRI, like collagen-based molecular MRI,[3] may be suitable for noninvasive monitoring of ECM remodeling during liver fibrosis. As the collagen-to-elastin-ratio changes during the progression and regression of liver fibrosis,[2] the selective or combined use of different molecular MR probes might be a promising strategy for translating the differential regulation of ECM proteins during fibrosis pro- and regression into novel noninvasive imaging techniques for the clinic. Supported by the German Research Foundation (DFG SFB/TRR57; TA434/2-1; LY294002 EH412/1-1; LA2937/1-1) and British Heart Foundation (RG/12/1/29262). ESMA was kindly provided by David Onthank (Lantheus Medical Imaging, North Billerica, MA). “
“The mechanism of idiosyncratic drug-induced liver injury (IDILI) remains poorly understood, to a large degree because of the lack of a valid animal model. Recently, we reported an animal model in which treatment of female C57BL/6 mice with amodiaquine (AQ) resulted in mild liver injury with a delayed onset and resolution despite continued treatment. Such adaptation is a common medchemexpress outcome in the IDILI caused by drugs that can cause liver failure. We had hypothesized that most IDILI is immune mediated and adaptation represents immune tolerance. In this study

we found that AQ treatment of Cbl-b-/- and PD-1-/- mice, which have impaired immune tolerance, resulted in a slightly greater injury. Co-treatment of C57BL/6 with AQ and anti-CTLA4 also resulted in a greater increase in ALT than treatment with AQ alone; however, these mice also had an increase in Treg cells, and T helper cells expressing PD-1 and CTLA4. The increase in these cells implies the induction of immune tolerance, and the ALT activity in these mice returned to normal despite continued treatment. Co-treatment of PD-1-/- mice with anti-CTLA4 antibody and AQ resulted in the greatest increase in ALT (200 – 300 U/L), and necroinflammatory responses characterized by portal infiltration of lymphocytes with interface hepatitis.