László Kóbori

Hormonal regulation of CYP1A expression

Aryl hydrocarbon receptor (AhR) is primarily involved in the transcriptional regulation of CYP1A enzymes, which are the main catalysts of the metabolic activation or inactivation of numerous procarcinogens, carcinogens, environmental toxicants, or therapeutic agents. Several endogenous factors, including hormones, can modify CYP1A induction, directly influencing CYP1A gene expression or AhR function or indirectly via crosstalks with other transcription factors. In this article, we summarize the current knowledge about the role of hormones (i.e., glucocorticoids, estrogens, progesterone, androgens, insulin, and glucagon) and hormone receptors as well as other essential factors (e.g., vitamin D, retinoids) in the modulation of CYP1A expression.

Interspecies differences in acetaminophen sensitivity of human, rat, and mouse primary hepatocytes

Most of the experiments studying acetaminophen (APAP) induced hepatotoxicity were performed using moue as model specie, right because its high sensitivity. While the toxic responses can be called forth easily in mice, the human relevancy of these results is questionable. In this study human, rat, and mouse primary hepatocytes were treated with increasing concentrations of APAP, and cell viability was measured by MTT cytotoxicity assay. Pronounced interspecies differences were obtained in cell viability following 24h of APAP treatment starting at 24h after seeding (EC50: 3.8mM, 7.6mM, and 28.2mM, in mouse, rat, and human hepatocyte culture, respectively). The longer time of culturing highly increased the resistance of hepatocytes of all species investigated. In rat hepatocyte culture EC50 values were 6.0mM, 12.5mM, and 18.8mM, when starting APAP treatment after 24, 48, and 72 h of seeding. Although N-acetylbenzoquinoneimine, a minor metabolite of APAP, which is mainly formed by CYP2E1 at high APAP concentration in every species studied, is thought to initiate the toxic processes, no correlation was found between CYP2E1 activities and hepatocyte sensitivity of different species. We conclude that the toxicity induced by APAP overdose highly depends on the animal model applied.

The effect of synthetic glucocorticoid, dexamethasone on CYP1A1 inducibility in adult rat and human hepatocytes

Glucocorticoids act synergistically with polycyclic aromatic hydrocarbons in increasing mRNA and protein levels of CYP1A1 in rat liver. The action of dexamethasone to modify CYP1A1 expression has been investigated in adult human hepatocytes. The effect of dexamethasone on the induction of CYP1A1 by 3‐methylcholanthrene is different in rat and human liver cells. Dexamethasone potentiates the induction of CYP1A1 about 3‐ to 4‐fold in rat cells. In human hepatocytes, it reduces CYP1A1 induction by 50–60% at enzyme protein level, while it does not have an effect on CYP1A1 mRNA amount.

Liver transplantation for hepatic metastases of neuroendocrine pancreatic tumors: a survival-based analysis.

Background. Liver transplantation (LT) has been accepted as a treatment in selected cases of neuroendocrine tumors (NETs) with hepatic metastases. Patients and Methods. A systematic review of the literature was conducted to evaluate long-term patient survival in the instances of LT for pancreatic NET. Univariate and multivariate regression analyses and survival analysis were performed. Results. Fifty-three clinical studies were screened. Data from 20 studies encompassing 89 transplanted patients were included in the study. Most primary tumors were endocrine pancreatic tumors (n=69), with gastrinomas representing the most frequent diagnosis (n=21). There were 61 functioning pancreatic NET. Simultaneous LT and pancreatic NET resections were performed in 45 instances. Cumulative 1-, 3-, and 5-year survival was 71%, 55%, and 44%, respectively, with a calculated mean survival of 54.45±6.31 months. Vasoactive intestinal peptide (VIPomas) had the best overall survival. Recurrence-free survival at 1, 3, and 5 years was 84%, 47%, and 47%, respectively. Recipient age more than or equal to 55 years (P=0.0242) and simultaneous LT-pancreatic resection (P=0.0132) were found to be significant predictors of worse survival by both univariate and multivariate Cox proportional hazard analyses. A scoring system was developed, with prognostic points assigned as follows: age more than or equal to 55 years:age less than 55years=1:0 points and simultaneous LT-pancreatic resection:LT alone=1:0 points. This stratification delineated three separate population samples corresponding to patients with scores of 0, 1, and 2, respectively. The calculated 5-year survival for scores 0, 1, and 2 was 61%, 40%, and 0%, respectively (P=0.0023). Conclusions. Despite the limitations of this retrospective analysis, good results can be achieved even for pancreatic NET primaries if the above-proposed scoring system is applied.

Splenic artery aneurysms in liver transplant patients

Abstract Background/Aims: The purpose of the study was to investigate the incidence of and risk factors for splenic artery aneurysms in liver transplant patients. Methods: Medical records and the pre- and 1-year postoperative angiograms of 337 liver transplant patients were reviewed to assess the presence and characteristics of these aneurysms. Results: Forty-five patients with aneurysms were identified (13%): 41 cases in 242 adult patients (17%) and four (4%) in 95 children ( p p p Conclusions: The incidence of splenic artery aneurysms in liver transplant patients is 13%. They are generally multiple and located in the distal third of the splenic artery. The incidence is higher in women and in patients with parenchymal liver disease and portal hypertension. The incidence of rupture was 4%.

Dehydroepiandrosterone Induces Human CYP2B6 through the Constitutive Androstane Receptor

Dehydroepiandrosterone (DHEA), the major precursor of androgens and estrogens, has several beneficial effects on the immune system, on memory function, and in modulating the effects of diabetes, obesity, and chemical carcinogenesis. Treatment of rats with DHEA influences expression of cytochrome P450 (P450) genes, including peroxisome proliferator-activated receptor α (PPARα)- and pregnane X receptor (PXR)-mediated induction of CYP4As and CYP3A23, and suppression of CYP2C11. DHEA treatment elevated the expression and activities of CYP3A4, CYP2C9, CYP2C19, and CYP2B6 in primary cultures of human hepatocytes. Induction of CYP3A4 in human hepatocytes was consistent with studies in rats, but induction of CYP2Cs was unexpected. The role of PXR in this response was studied in transient transfection assays. DHEA activated hPXR in a concentration-dependent manner. Because CYP2B6 induction by DHEA in human hepatocytes might involve either PXR or constitutive androstane receptor (CAR) activation, we performed experiments in primary hepatocytes from CAR knockout mice and observed that CAR was required for maximal induction of Cyp2b10 by DHEA. Furthermore, CAR-mediated Cyp2b10 induction by DHEA was inhibited by the inverse agonist of CAR, androstanol (5α-androstan-3α-ol). Further evidence for CAR activation was provided by cytoplasmic/nuclear transfer of CAR upon DHEA treatment. Elucidation of CAR activation and subsequent induction of CYP2B6 by DHEA presented an additional mechanism by which the sterol can modify the expression of P450s. The effect of DHEA on the activation of the xenosensors PPARα, PXR, and CAR, and the consequent potential for adverse drug/toxicant interactions should be considered in humans treated with this nutriceutical agent.

Multidrug Resistance Protein 2-Mediated Estradiol-17β-D-glucuronide Transport Potentiation : In Vitro-in Vivo Correlation and Species Specificity

Multidrug resistance protein 2 (MRP2) is a multispecific organic anion transporter expressed at important pharmacological barriers, including the canalicular membrane of hepatocytes. At this location it is involved in the elimination of both endogenous and exogenous waste products, mostly as conjugates, to the bile. Estradiol-17β-d-glucuronide (E217βG), a widely studied endogenous substrate of MRP2, was shown earlier to recognize two binding sites of the transporter in vesicular transport assays. MRP2 modulators (substrates and nonsubstrates) potentiate the transport of E217βG by MRP2. We correlated data obtained from studies of different complexities and investigated the species-specific differences between rat and human MRP2-mediated transport. We used vesicular transport assays, sandwich-cultured primary hepatocytes, and in vivo biliary efflux in rats. Our results demonstrate that the rat Mrp2 transporter, unlike the human MRP2, transports E217βG according to Michaelis-Menten type kinetics. Nevertheless, in the presence of modulator drugs E217βG transport mediated by the rat transporter also shows cooperative kinetics as potentiation of E217βG transport was observed in the vesicular transport assay. We also demonstrated that the potentiation exists both in rat and in human hepatocytes and in vivo in rats.

Analysis of differences in outcome of two European liver transplant centers

Authors analyzed the differences in the outcome of two European liver transplant centers differing in case volume and experience. The first was the Transplantation and Surgical Clinic, Semmelweis University, Budapest, Hungary (SEB) and the second the University Medical Center Groningen, Groningen, The Netherlands (UMCG). We investigated if such differences could be explained. The 1‐, 3‐ and 5‐year patient survival in the UMCG was 86%, 80%, and 77% compared with 65%, 56%, and 55% in SEB. Graft survival at the same time points was 79%, 71%, and 66% in the UMCG and 62%, 55%, and 53% in SEB. Significant differences were present regarding the donor and recipient age, diagnosis mix, disease severity and operation variables, per‐operative transfusion rate, vascular complications, postoperative infection rate, and need for renal replacement. To determine factors correlating with survival, a separate uni‐ and multivariate analysis was performed in each center individually, between study parameters and patient survival. In both centers, peri‐operative red blood cell (RBC) transfusion rate was a significant predictor for patient survival. The difference in blood loss can be explained by different operation techniques and shorter operation time in SEB, with consequently less time spent on hemostasis. It was jointly concluded that measures to reduce blood loss by adapting the operation technique might lead to improved survival and reduced morbidity.

Epidural Anesthesia? No of Course

Although the contraindications for thoracic epidural anesthesia (TEA) are well defined, the debate continues about whether TEA improves outcomes. Pro and con trials and a metaanalysis in the past have yielded equivocal results; they did not deal with new vascular intervention or drugs. The benefit of TEA in surgery is to provide analgesia. In subgroups, TEA can decrease the mortality and morbidity. In contrast, the cost can increase in the situation of a complication that is opposite to the side effects is rare, but the impairment caused by them is out of proportion to the benefits. Primary or secondary prophylaxis with antithrombotic drugs is increasing in developed countries because of the increasing cardiovascular interventions and aging of the population. The neuroaxial guidelines are useful, but the changing of the coagulation profile after hepatectomy is not included in them. The decision to use TEA in liver surgery must be individualized with steps planned from the beginning. TEA suitability is based on an evaluation of the contraindications, comorbidities, coagulation profiles, hepatic reserve, and balance of benefits and risks. The insertion or withdrawal of the epidural catheter should be made with care according to the neuroaxial guidelines and in the presence of a normal TEG. The decreasing level of prothrombin content and platelet counts after hepatectomy should be closely monitored every 2 to 5 days.

Outcome of liver transplantation based on donor graft quality and recipient status.

BACKGROUND Availability of suitable donor organs has always limited the number of liver transplantations performed. Use of marginal donor organs is an alternative to overcome organ shortage. OBJECTIVE To analyze the effect of various combinations of donor organ quality and recipient status on the outcome of liver transplantation. MATERIALS AND METHODS Data from 260 whole-liver transplantations performed between January 2003 and September 2009 were analyzed retrospectively. Study groups were established according to donor organ quality (marginal score 0-1 vs 2-5) and recipient status (Model for End-Stage Liver Disease [MELD] score <17 or >17). In patients at low risk, 102 received optimal grafts (good-to-good group [G/G], and 75 received marginal grafts (bad-to-good group [B/G]. In patients at high risk, 46 received optimal grafts (good-to-bad group [G/B], and 37 received marginal grafts (bad-to-bad group [B/B]. RESULTS No differences were observed in cumulative patient and graft survival rates; however, total survival differed in the early period after transplantation, that is, within 1 year. There was a higher rate of overall postoperative complications including initial poor graft function, bleeding, infection, and kidney failure in group B/B compared with group G/B (25 of 37 patients [67.5%] vs 27 of 46 patients [59.0%]), group B/G (25 of 37 patients [68%] vs 39 of 75 patients [52%], and group G/G (25 of 37 patients [68%] vs 43 of 102 patients [42%]) (P = .04). Patients with a high MELD score (G/B and B/B) demonstrated increased risk of postoperative complications. Use of donor organs with marginal score of 2 or higher in patients with high MELD scores increased early patient mortality. CONCLUSION In summary, patients with a high MELD score (G/B and B/B) are at an increased risk of post-OLT complications. In contrast, use of marginal grafts (B/G and B/B) increased the rate of hepatitis C virus recurrence and decreased the response rate to antiviral therapy. The combination of impaired donor grafts and recipients at high risk should be avoided.