Tolvaptan reduces the required amount of albumin infusion in patients with decompensated cirrhosis with uncontrolled ascites : a multicenter retrospective propensity score-matched cohort study.

Background: The aim of this retrospective study was to determine whether tolvaptan treatment reduces the amount of albumin administered, volume of ascites removed, and frequency of paracentesis procedures in patients with decompensated cirrhosis with uncontrolled ascites with conventional diuretics. Patients and methods: The control (C) group included patients treated with conventional diuretics. The tolvaptan (T) group included patients treated with both tolvaptan and conventional diuretics. Both groups were matched according to baseline parameters. The amount of albumin administered, volume of ascites removed, and frequency of paracentesis within 30 days of onset of uncontrolled ascites were compared between the two groups. Results: After matching, 74 patients (C=37, T=37) were included. Baseline parameters (C vs. T group) were as follows: age, 69.5 ± 9.3 vs. 70.4 ± 11.0 years (p = 0.702) ; males, 24 (64.9%) vs. 25 (67.6%) (p = 0.999) ; patients with hepatocellular carcinoma, 17 (45.9%) vs. 18 (48.6%) (p = 0.999) ; serum albumin levels at treatment initiation, 2.76 ± 0.48 vs. 2.73 ± 0.49 g/dL (p = 0.773), and serum creatinine levels at treatment initiation, 1.18 ± 1.23 vs. 1.09 ± 0.48 g/dL (p = 0.679). In the C vs. T groups, respectively, mean amount of albumin administered was 51.0 ± 31.4 vs. 33.4 ± 29.8 g/month (p = 0.016) ; mean volume of ascites removed was 2,905 ± 4,921 vs. 1,824 ± 3,185 mL/month (p = 0.266) ; and mean frequency of paracentesis was 0.92 ± 1.46 vs. 0.89 ± 1.45 procedures (p = 0.937). Conclusions: Tolvaptan reduced the use of albumin infusion in patients with decompensated cirrhosis and was effective and acceptable for uncontrolled ascites.

A change in the timing for starting systemic therapies for hepatocellular carcinoma: the comparison of sorafenib and lenvatinib as the first-line treatment.

Aim: The aim of this retrospective multicenter study was to evaluate the differences in the timing for starting systemic therapies as the first-line treatment for hepatocellular carcinoma (HCC). Methods: A total of 375 patients with HCC treated with sorafenib from May 2009 to March 2018 and 56 patients treated with lenvatinib from March 2018 to November 2018 at our affiliated hospitals were included in this study. Results: The median ages of the sorafenib and lenvatinib groups were 71.0 (interquartile range [IQR]: 64.0-77.0) and 73.5 (IQR: 68.0 -80.0) years old, and 300 (80.0%) and 42 (75.0%) patients were men, respectively. The Barcelona Clinic Liver Cancer stage was early, intermediate and advanced in 39 patients (10.4%), 133 patients (35.5%) and 203 patients (54.1%) in the sorafenib group and 1 patient (1.8%), 17 patients (30.4%) and 38 patients (67.9%) in the lenvatinib group, respectively. In the analysis of intermediate HCC, patients who satisfied the criteria of TACE failure/refractoriness (P=0.017), those with ALBI grade 1 (P=0.040), and those with a serum AFP level < 200 ng/ml (P=0.027) were found more frequently in the lenvatinib group than in the sorafenib group, with statistical significance. The objective response rate (ORR) of lenvatinib was 34.8% in the overall patients and 46.7% in the intermediate-stage HCC patients, which was significantly higher than sorafenib (P=0.001, P=0.017). Conclusions: The emergence of lenvatinib has encouraged physicians to start systemic chemotherapy earlier in intermediatestage HCC patients.

Clinical features and treatment of nonalcoholic fatty liver disease across the Asia Pacific region-the GO ASIA initiative.

BACKGROUND: The Gut and Obesity Asia (GO ASIA) workgroup was formed to study the relationships between obesity and gastrointestinal diseases in the Asia Pacific region. AIM: To study factors associated with nonalcoholic steatohepatitis (NASH) and advanced fibrosis, and medical treatment of biopsy-proven nonalcoholic fatty liver disease (NAFLD) patients. METHODS: Retrospective study of biopsy-proven NAFLD patients from centres in the GO ASIA Workgroup. Independent factors associated with NASH and with advanced fibrosis on binary logistic regression analyses in a training cohort were used for the development of their corresponding risk score, which were validated in a validation cohort. RESULTS: We included 1008 patients from nine centres across eight countries (NASH 62.9%, advanced fibrosis 17.2%). Independent predictors of NASH were body mass index ≥30 kg/m2 , diabetes mellitus, dyslipidaemia, alanine aminotransferase ≥88 U/L and aspartate aminotransferase ≥38 U/L, constituting the Asia Pacific NASH risk score. A high score has a positive predictive value of 80%-83% for NASH. Independent predictors of advanced fibrosis were age ≥55 years, diabetes mellitus and platelet count <150 × 109 /L, constituting the Asia-Pacific NAFLD advanced fibrosis risk score. A low score has a negative predictive value of 95%-96% for advanced fibrosis. Only 1.7% of patients were referred for structured lifestyle program, 4.2% were on vitamin E, and 2.4% were on pioglitazone. CONCLUSIONS: More severe liver disease can be suspected or ruled out based on factors identified in this study. Utilisation of structured lifestyle program, vitamin E and pioglitazone was limited despite this being a cohort of biopsy-proven NAFLD patients with majority of patients having NASH.

Observation and determination of periodontal tissue profile using optical coherence tomography.

BACKGROUND AND OBJECTIVE: Diagnosis is a crucial step in periodontal treatment. The aim of this study was to evaluate the effectiveness of optical coherence tomography (OCT) for observation and determination of periodontal tissue profiles in vivo. MATERIAL AND METHODS: In experiment 1, refractive indices of purified water, porcine gingiva and human gingiva at 1330 nm were determined for the analysis of OCT images of periodontal tissues. In experiment 2, OCT examination was performed in the midlabial apico-coronal plane of mandibular anteriors in 30 Asian volunteers with healthy gingiva. Sulcus depth was measured on intra-oral photographs taken during probing. In the OCT images, the gingival, epithelial and connective tissue thickness, and the position of alveolar bone crest were determined and finally, the biologic width was measured. RESULTS: Refractive indices of purified water, porcine gingiva and human gingiva were 1.335, 1.393 and 1.397, respectively. Cross-sectional images of gingival epithelium, connective tissue and alveolar bone were depicted in real-time. The sulcular and junctional epithelium could be visualized occasionally. Laser penetration and reflection were limited to a certain depth with an approximate maximal imaging depth capability of 1.5 mm and OCT images of the periodontal structure were not clear in some cases. The average maximal thickness of gingiva and epithelium and biologic width at the mandibular anteriors were 1.06 ± 0.21, 0.49 ± 0.15 and 2.09 ± 0.60 mm, respectively. CONCLUSION: OCT has promise for non-invasive observation of the periodontal tissue profile in detail and measurement of internal periodontal structures including biologic width in the anterior region.

Faecal lactoferrin is a useful biomarker for mucosal healing in patients with ulcerative colitis during granulocyte and monocyte adsorptive apheresis therapy.

AIM: The study investigated the value of faecal lactoferrin as a follow-up biomarker for mucosal healing of ulcerative colitis during granulocyte and monocyte adsorptive apheresis (GMA) therapy. METHOD: Patients with ulcerative colitis exhibiting a moderate or severe disease activity with a partial Mayo Score (pMS) of over 4 were enrolled in this study. The patients received 10 courses of GMA therapy. The pMS value and faecal lactoferrin level were monitored and compared with the findings of endoscopy until 12 months after the last dose of GMA therapy. RESULTS: Twenty patients (male:female 11:9) were enrolled in this study. Twelve had total colitis, while six had left-sided involvement and two had distal proctitis. Thirteen (65.0%) responded to GMA therapy. The faecal lactoferrin levels were significantly decreased in patients who responded to GMA therapy (P < 0.05), whereas the levels did not change in non-responders. Moreover, the faecal lactoferrin levels correlated with the endoscopic findings (r = 0.792, P < 0.01) and pMS scores (r = 0.529, P < 0.01). The correlation coefficients between the faecal lactoferrin levels and mucosal findings were higher than those observed between the pMS score and mucosal findings. CONCLUSION: The faecal lactoferrin level is a useful biomarker of the mucosal findings in ulcerative colitis. Although endoscopy is the gold standard, the faecal lactoferrin level can be used as a biomarker during GMA therapy in patients with ulcerative colitis.

Percutaneous radiofrequency ablation for hepatocellular carcinoma located in the caudate lobe of the liver.

AIM: This study aimed to evaluate the effectiveness and safety of radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) located in the caudate lobe of the liver. PATIENTS AND METHODS: Between 2012 April and 2014 February, 142 patients with HCC meeting the Milan criteria were enrolled in this study. Of these patients, nine patients had HCC located in the caudate lobe (caudate group). Six of the nine cases were located in the Spiegel lobe, two cases were located in the paracaval portion and one case was located in the caudate process. We evaluated the local recurrence rate and RFA-related complications in the caudate group and non-caudate group. RESULTS: The local recurrence rate in the caudate group was 12.5% at 1 year and 12.5% at 2 years, while the local recurrence rate in the non-caudate group was 14.9% at 1 year and 29.0% at 2 years; there were no significant differences between the groups. No complications were observed in the caudate group, and minor complications were observed in six patients (4.5%) in the non-caudate group. No major complications or mortalities were observed in either group, and the complication rates were not significantly different between the groups (P = 1). CONCLUSIONS: RFA for HCC in the caudate lobe and the non-caudate lobe has equivalent effectiveness and safety. RFA is a promising treatment option for HCC arising in the caudate lobe.

Delivery of siRNA to the brain using a combination of nose-to-brain delivery and cell-penetrating peptide-modified nano-micelles.

The potential for RNA-based agents to serve as effective therapeutics for central nerve systems (CNS) disorders has been successfully demonstrated in vitro. However, the blood-brain barrier limits the distribution of systemically administered therapeutics to the CNS, posing a major challenge for drug development aimed at combatting CNS disorders. Therefore, the development of effective strategies to enhance siRNA delivery to the brain is of great interest in clinical and pharmaceutical fields. To improve the efficiency of small interfering RNA (siRNA) delivery to the brain, we developed a nose-to-brain delivery system combined with cell-penetrating peptide (CPP) modified nano-micelles comprising polyethylene glycol-polycaprolactone (PEG-PCL) copolymers conjugated with the CPP, Tat (MPEG-PCL-Tat). In this study, we describe intranasal brain delivery of siRNA or dextran (Mw: 10,000 Da) as a model siRNA, by using MPEG-PCL-Tat. Intranasal delivery of dextran with MPEG-PCL-Tat improved brain delivery compared to intravenous delivery of dextran either with or without MPEG-PCL-Tat. We also studied the intranasal transfer of MPEG-PCL-Tat to the brain via the olfactory and trigeminal nerves, the putative pathways to the brain from the nasal cavity. We found that MPEG-PCL-Tat accelerated transport along the olfactory and trigeminal nerve pathway because of its high permeation across the nasal mucosa.

Azelnidipine is a calcium blocker that attenuates liver fibrosis and may increase antioxidant defence.

BACKGROUND AND PURPOSE: Oxidative stress plays a critical role in liver fibrogenesis. Reactive oxygen species (ROS) stimulate hepatic stellate cells (HSCs), and ROS-mediated increases in calcium influx further increase ROS production. Azelnidipine is a calcium blocker that has been shown to have antioxidant effects in endothelial cells and cardiomyocytes. Therefore, we evaluated the anti-fibrotic and antioxidative effects of azelnidipine on liver fibrosis. EXPERIMENTAL APPROACH: We used TGF-ß1-activated LX-2 cells (a human HSC line) and mouse models of fibrosis induced by treatment with either carbon tetrachloride (CCl(4) ) or thioacetamide (TAA). KEY RESULTS: Azelnidipine inhibited TGF-ß1 and angiotensin II (Ang II)-activated α1(I) collagen mRNA expression in HSCs. Furthermore, TGF-ß1- and Ang II-induced oxidative stress and TGF-ß1-induced p38 and JNK phosphorylation were reduced in HSCs treated with azelnidipine. Azelnidipine significantly decreased inflammatory cell infiltration, pro-fibrotic gene expressions, HSC activation, lipid peroxidation, oxidative DNA damage and fibrosis in the livers of CCl(4) - or TAA-treated mice. Finally, azelnidipine prevented a decrease in the expression of some antioxidant enzymes and accelerated regression of liver fibrosis in CCl(4) -treated mice. CONCLUSIONS AND IMPLICATIONS: Azelnidipine inhibited TGF-ß1- and Ang II-induced HSC activation in vitro and attenuated CCl(4) - and TAA-induced liver fibrosis, and it accelerated regression of CCl(4) -induced liver fibrosis in mice. The anti-fibrotic mechanism of azelnidipine against CCl(4) -induced liver fibrosis in mice may have been due an increased level of antioxidant defence. As azelnidipine is widely used in clinical practice without serious adverse effects, it may provide an effective new strategy for anti-fibrotic therapy.

Endoscopic submucosal dissection for colorectal tumors.

BACKGROUND: Endoscopic submucosal dissection (ESD) is a state-of-the-art method that enables resection of larger tumors than those resectable by conventional endoscopic mucosal resection (EMR). However, the individual role of each method in the treatment of colorectal tumors remains undetermined. OBJECTIVE AND METHODS: To consider the respective indications of ESD and EMR for colorectal tumors, we analyzed the results of the two treatments retrospectively. RESULTS: Tumors treated by ESD (44 tumors) were significantly larger, more often located in the rectum and more often coexistent with cancer than those treated by EMR (512 tumors). EMR was used in the majority of adenomas, and showed high rates of both one-piece resection (OPR) and complete resection (CR) for adenomas less than 20 mm. However, for adenomas and cancers greater or equal to 20 mm, the CR rate for EMR was significantly lower than that for ESD because of the incidence of OPR with a positive lateral margin (16% vs 0% with ESD vs EMR). Histopathology (cancer), size (> or =20 mm) and macroscopic type (laterally spreading tumors) were shown to be significant risk factors for that incidence. For tumors with these factors, ESD showed a higher CR rate than did EMR. However, ESD required longer operating times and tended to have a higher rate of perforation compared with EMR. ESD was aborted halfway in seven cases due to technical difficulties and perforation. CONCLUSION: ESD and EMR have different characteristics as treatment for colorectal tumors. Careful evaluation of the lesion and of the balance between benefits and risks are mandatory before selecting either of these treatments for colorectal tumors.

Endoscopic submucosal dissection for rectal tumors.

BACKGROUND AND STUDY AIM: Endoscopic submucosal dissection (ESD) has recently been developed for one-piece resection of gastric tumors. In order to improve patients' quality of life, it may be desirable to use the same technique for rectal tumors. METHODS: 35 consecutive patients with rectal tumors were enrolled. ESD was carried out using the same technique as for the stomach. The efficacy, technical feasibility, operation time, complications, and follow-up results were assessed. RESULTS: The mean size of the epithelial tumors was 26.2 +/- 14.0 mm, and the rates of one-piece resection and one-piece resection with tumor-free margins were 73.3% (22 of 30) and 70.0% (21 of 30), respectively. The median operation time was 70 min (range 8-360 min). All five carcinoid tumors were completely resected. No patient needed blood transfusion or had the complication of problematic bleeding. Perforation during ESD occurred in one patient (2.9%), who was managed with conservative medical treatment after endoscopic closure of the perforation. Excluding seven patients, who either underwent additional surgery or whose follow-up period was less than 1 year, all 23 patients with epithelial tumors were free of recurrence during a mean follow-up period of 25.7 months (range 12-53 months). CONCLUSIONS: ESD was thus found to be feasible for the treatment of rectal tumors, with promising results although the follow-up periods were short. ESD may therefore be indicated for rectal tumors which are not resectable en bloc by conventional procedures, in order to improve the patients' quality of life.

Endoscopic submucosal dissection for early gastric cancers and large flat adenomas.

BACKGROUND AND STUDY AIM: Endoscopic submucosal dissection (ESD) is a new diagnostic and treatment technique for early gastric cancer (EGC). The present study aims to identify the technical feasibility, operation time, and complications associated with ESD. METHODS: We reviewed the patients who underwent ESD for EGCs at Maebashi Red Cross Hospital. RESULTS: There were 160 patients with 171 EGCs treated by ESD. The mean age was 71.4 +/- 8.9 years (median 72). The rate for one-piece resection with tumor-free margins was 94.2 % (161/171), and was 93.2 % (82/88) for large lesions (> 20 mm) and 92.1 % (35/38) for ulcerative lesions. The median operation time was 80 min (range 10-600 min). Evidence of immediate bleeding was found in 2.9 % (5/171), delayed bleeding was seen in 7.6 % (13/171), and perforation was observed in 3.5 % (6/171) of the lesions. All patients with complications, including perforation, were successfully treated endoscopically. There were no local or distant metastases in the lesions which met our indication criteria for ESD. CONCLUSION: The present study shows the technical feasibility of ESD, which provides the capability of one-piece resection even in large and ulcerative lesions.

Primary biliary cirrhosis complicated with sigmoid colonic varices: the usefulness of computed tomographic angiography.

Gastroesophageal varices are the major complication of portal hypertension. Ectopic varices develop in various organs such as the duodenum, colon, and gallbladder. However, varices other than at gastroesophageal or rectal sites is a rare entity. We report a 53-year-old patient with primary biliary cirrhosis complicated by sigmoid colonic varices. Computed tomographic angiography was useful to understand the entire status of the varices.

A ligand for peroxisome proliferator activated receptor gamma inhibits cell growth and induces apoptosis in human liver cancer cells.

BACKGROUND AND AIMS: Induction of apoptosis of cancer cells through ligands of nuclear hormone receptors (NHRs) is a new approach in cancer therapy. Recently, one of the NHRs, peroxisome proliferator activated receptor gamma (PPARgamma), has been shown to influence cell growth in certain cancer cells although its effect on hepatocellular carcinoma (HCC) has not been analysed. METHODS: Experiments were conducted using three human liver cancer cell lines, PLC/PRF/5, Hep G2 and HuH-7, in vitro. These cells were exposed to troglitazone, a synthetic ligand for PPARgamma, and the effects on cell growth were analysed. RESULTS: Expression of PPARgamma mRNA was detected in all three liver cancer cell lines. Activation of PPARgamma by troglitazone caused a marked growth inhibition in a dose dependent manner in three hepatoma cell lines. The DNA fragmentation ELISA assay and Hoechst 33258 staining revealed that the growth inhibitory effect by adding troglitazone was due to apoptosis of PLC/PRF/5, which strongly expressed PPARgamma. Troglitazone also induced activation of the cell death protease, caspase 3, but not caspase 8, in PLC/PRF/5 cells. However, expression levels of antiapoptotic factor bcl-2 and apoptosis inducing factor bax were not affected. CONCLUSION: Our study showed that PPARgamma was expressed in human liver cancer cells and that the ligand for PPARgamma, troglitazone, inhibited the growth of these cells by inducing apoptosis through caspase 3 activation, indicating that troglitazone could be potentially useful as an apoptosis inducer for the treatment of HCC.

Effect of alpha-tocopherol on hepatocarcinogenesis in transforming growth factor-alpha (TGF-alpha) transgenic mice treated with diethylnitrosamine.

To examine the potentially chemopreventive effects of alpha-tocopherol on hepatocarcinogenesis, we fed the transgenic mice line MT42, which overexpresses transforming growth factor-alpha (TGF-alpha) and which has been established as having a high incidence of liver tumor, with different concentrations of alpha-tocopherol and examined the hepatic tumorigenesis of these mice. At 3 weeks of age, MT42 male mice received a single intraperitoneal injection of diethylnitrosamine (DEN), 5 mg/kg body weight, to initiate the formation of liver tumors. The mice were divided into three groups: group A, control diet (20 mg/kg of alpha-tocopherylacetate); group B, deficient diet (less than 1 mg/kg); group C, supplemented diet (500 mg/kg). Neoplastic change was determined at 40 weeks of age. The incidence of adenomas (p < 0.05), the maximum tumor size (p < 0.01), the mean relative liver weight (p < 0.01), and the proliferating cell nuclear antigen (PCNA) labeling indices of the non-tumor sites (p < 0.01) of group B were significantly higher than those of group C. No toxic effects of alpha-tocopherol were found. Alpha-tocopherol-deficient diet accelerated the hepatocarcinogenesis of TGF-alpha transgenic mice treated with DEN. At best, these data demonstrate that alpha-tocopherol-deficiency is not beneficial for prevention of hepatocarcinogenesis in this model. Alpha-tocopherol may be useful for the chemoprevention for liver cancer.

Zinc supplementation enhances the response to interferon therapy in patients with chronic hepatitis C.

We evaluated the synergistic effect of zinc supplementation on the response to interferon (IFN) therapy in patients with intractable chronic hepatitis C in a pilot study using natural IFN-alpha with or without zinc. No clinical differences were observed between patients treated with IFN alone (n=40) and IFN with polaprezinc (IFN + Zn, n=35). All patients were positive for HCV genotype Ib and had more than 105 copies of the virus/mL serum. Ten million units of natural IFN-alpha was administered daily for 4 weeks followed by the same dose every other day for 20 weeks. In the IFN + Zn group, patients received an additional dose of 150 mg/day polaprezinc orally throughout the 24-week IFN course. No additional side-effects of polaprezinc were noted but four out of 40 IFN alone treatment and three out of 35 IFN + Zn group withdrew because of side-effects. Complete response (CR) was defined as negative HCV RNA in the serum on PCR and normal aminotransferase level 6 months after therapy. Incomplete response (IR) was normal liver enzyme and positive serum HCV RNA. Both of them were evaluated at the 6 months after the completion of the treatment. Patients with higher levels of serum HCV (more than 5 x 105 copies/mL) had little response in both treatment groups. Patients with moderate amount of HCV (105 to 4.99 x 105/mL) showed high response rates in combination group (CR: 11/27, 40.7%; CR + IR 15/27, 64.3%), better than IFN alone (CR: 2/15, 18.2%; CR + IR: 2/15, 18.2%). Serum zinc levels were higher in patients with IFN + Zn group than in the IFN group. Our results indicate that zinc supplementation enhances the response to interferon therapy in patients with intractable chronic hepatitis C.

The phenobarbital response enhancer module in the human bilirubin UDP-glucuronosyltransferase UGT1A1 gene and regulation by the nuclear receptor CAR.

The UDP-glucuronosyltransferase, UGT1A1, is the critical enzyme responsible for detoxification of the potentially neurotoxic bilirubin by conjugating it with glucuronic acid. For decades, phenobarbital (PB) treatment for hyperbilirubinemia has been known to increase expression of the UGT1A1 gene in liver. We have now delineated the PB response activity to a 290-bp distal enhancer sequence (-3483/-3194) of the UGT1A1 gene. The enhancer contains 3 putative nuclear receptor motifs, and it was activated by the nuclear orphan receptor, human constitutive active receptor (hCAR), in cotransfected HepG2 cells. Bacterially expressed hCAR, acting as a heterodimer with in vitro-translated retinoid X receptor (RXRalpha), only bound to 1 of the 3 NR motifs, named gtNR1 in a gel-shift assay. Consistently, mutations of the gtNR1 site significantly decreased the activation by hCAR of the 290-bp DNA in transfection assays. Moreover, the 290-bp DNA was effectively activated in mouse primary hepatocytes in response to PB, offering an excellent clinical test for the examination of the responsiveness of the UGT1A1 to PB in the human population, particularly individuals with hyperbilirubinemia.

Estrogen activation of the nuclear orphan receptor CAR (constitutive active receptor) in induction of the mouse Cyp2b10 gene.

The nuclear orphan receptor CAR (constitutively active receptor or constitutive androstane receptor) can be activated in response to xenochemical exposure, such as activation by phenobarbital of a response element called NR1 found in the CYP2B gene. Here various steroids were screened for potential endogenous chemicals that may activate CAR, using the NR1 enhancer and Cyp2b10 induction in transfected HepG2 cell and/or in mouse primary hepatocytes as the experimental criteria. 17beta-Estradiol and estrone activated NR1, whereas estriol, estetrol, estradiol sulfate, and the synthetic estrogen diethylstilbestrol did not. On the other hand, progesterone and androgens repressed NR1 activity in HepG2 cells, and the repressed NR1 activity was fully restored by estradiol. Moreover, estrogen treatment elicited nuclear accumulation of CAR in the mouse livers, as well as primary hepatocytes, and induced the endogenous Cyp2b10 gene. Ovariectomy did not affect either the basal or induced level of CAR in the nucleus of the female livers, while castration slightly increased the basal and greatly increased the induced levels in the liver nucleus of male mice. Thus, endogenous estrogen appears not to regulate CAR in female mice, whereas endogenous androgen may be the repressive factor in male mice. Estrogen at pharmacological levels is an effective activator of CAR in both female and male mice, suggesting a biological and/or toxicological role of this receptor in estrogen metabolism. In addition to mouse CAR, estrogens activated rat CAR, whereas human CAR did not respond well to the estrogens under the experimental conditions.