Biomedical subjects

Peter Neuhaus

Publications and source records attributed to Peter Neuhaus.

At least 145 records · Page 8Linked to original sources

PubMed2002

Hepatocellular adenoma and focal nodular hyperplasia after long-term use of danazol for endometriosis: a case report.

Danazol, an inhibitor of pituitary gonadotropin with weak androgenic effect, is currently being used for the treatment of endometriosis. In contrast to other C17 alkylated anabolic steroids, it has been rarely associated with the occurrence of primary liver tumors. We present the case of a patient with endometriosis in whom a hepatocellular adenoma was discovered after 14 years of treatment with danazol for endometriosis. The patient showed no clinical signs of a liver tumor and it was only detected by ultrasonography and magnetic resonance imaging (MRI). When long-term danazol therapy is required, regular ultrasonography for monitoring and early tumor detection is recommended.

Adenoma, Liver Cell↗

PubMed2002

Distinct enzyme profiles in patients with cryptogenic cirrhosis reflect heterogeneous causes with different outcomes after liver transplantation (OLT): a long-term documentation before and after OLT.

BACKGROUND: Sound information is lacking about the clinical presentation of cryptogenic cirrhosis and its outcome after orthotopic liver transplantation (OLT). METHODS: Among 856 patients who have been transplanted at our center, 40 patients had no evidence of any known etiologies and were therefore defined as suffering from cryptogenic cirrhosis. Their median follow-up period before OLT was 78 months (range, 1-264), and after OLT 97 months (range, 1-132). Laboratory and histological data were evaluated according to features being compatible either with a toxic, hepatitic, or cholestatic condition. RESULTS: The clinical and histological findings differed specifically between these three groups. The toxic-like group (GGT 4-18 x upper limit of normal [ULN]) expressed significantly higher IgA levels, had histologically more often fatty liver changes, and risk factors for non-alcoholic steatohepatitis predominated (56% compared with 3% in the other groups, P=0.01). The hepatitic-like group (ALT 2-18 x ULN) showed histologically features of chronic hepatitis or hepatitic cirrhosis, and only among these patients a median International Autoimmune Hepatitis (IAH) score of 13 was found suggesting autoimmune hepatitis (AiH). In the cholestatic group (AP 2-8 x ULN) histology was compatible with a non-toxic inflammatory process but IAH score excluded AiH in all. After OLT, actuarial graft and patients survival was 90% at 5 years. Mild or moderate graft hepatitis occurred in 9 patients (23%) and was significantly associated with a pre-OLT IAH score >or= 10 (P =0.008). CONCLUSIONS: This study provides arguments that cryptogenic cirrhosis is a heterogeneous disease in which autoimmune mechanisms might be predominately involved and being responsible for recurrence of chronic liver disease observed in some instances after OLT.

Adult↗

PubMed2002

Inhibition of ischemia/reperfusion injury and chronic graft deterioration by a single-donor treatment with cobalt-protoporphyrin for the induction of heme oxygenase-1.

Today, the major problem in organ transplantation is not acute graft rejection but chronic graft deterioration. In addition to alloantigen-specific events, alloantigen independent factors like donor age, previous diseases, consequences of brain death, and perioperative events of ischemia/reperfusion injury have a major impact on long-term graft function. The induction of the stress protein heme oxygenase-1 (HO-1) protects cells from injury and apoptosis. Here, we tested the protective effects of HO-1 induction in a clinically relevant kidney transplant model. Induction of HO-1 expression following cobalt-protoporphyrin (CoPP) treatment in organ donors prolonged graft survival and long-term function remarkably following extended periods of ischemia. Positive effects were observed with both optimal and marginal grafts from old donor animals. Structural changes characteristic for chronic rejection, as well as graft infiltration by monocytes/macrophages and CD8+ T cells, were substantially reduced following HO-1 induction. Up-regulation of HO-1 expression before organ transplantation was also associated with reduced levels for tumor necrosis factor (TNF)-alpha mRNA, increased levels for interferon (IFN)-gamma, and bcl-x, and insignificant differences for CD25, interleukin (IL)-2, IL-4, IL-6, and IL-10 mRNA levels. The significant improvement of long-term graft function following induction of HO-1 expression in donor organs suggests that this strategy may be a novel clinical treatment option with particular relevance for transplantation of marginal organs.

Animals↗

PubMed2002

Preoperative evaluation of malignant liver tumors: comparison of unenhanced and SPIO (Resovist)-enhanced MR imaging with biphasic CTAP and intraoperative US.

The purpose of this study was to evaluate the diagnostic efficacy of iron-oxide-enhanced MRI vs CT during arterial portography (CTAP) and intraoperative ultrasound (IOUS) in detection of liver neoplasms. Seventeen patients with malignant focal liver lesions (liver metastases, n=7), hepatocellular carcinomas (HCC, n=9), and cholangiocellular carcinoma (CCC, n=1) underwent presurgical Resovist-enhanced MRI and CTAP. Two independent observers (A and B) assessed the blinded images of unenhanced and iron-oxide-enhanced MRI vs CTAP for the presence, number, and location of the liver lesions. These results were compared lesion by lesion and segment by segment with the results of intraoperative ultrasound ( n=17) serving as the reference standard. Eighty lesions were detected by intraoperative ultrasound in 17 patients. In comparison with IOUS (lesion-by-lesion analysis) the sensitivity was 86.8% for CTAP, 65% for combined unenhanced MR imaging, and 86.8% for combined Resovist-enhanced MRI as well as 86.8% for the combination of unenhanced and Resovist-enhanced MRI. Compared with the sensitivity of combined unenhanced MRI the sensitivity of CTAP as well as the sensitivity of combined Resovist-enhanced MRI was significantly higher (p<0.05). False-positive results were much higher in CTAP as compared with combined unenhanced and SPIO-enhanced MRI. Using the segment-by-segment analysis the specificity of combined unenhanced MRI with 100% (96.7-100%) as well as combined Resovist-enhanced MRI with 100% (96.7-100%) was significantly higher (p<0.05) in comparison with the specificity of CTAP with 91.1% (83.2-96.1%). The accuracy of combined unenhanced MRI was 100% (93.2-100%), combined Resovist-enhanced MRI 100% (93.6-100%) and of CTAP 85.2% (72.9-93.4%). In the detection of focal liver lesions iron-oxide-enhanced MR imaging is superior to unenhanced MRI and similar to CTAP.

Adult↗

PubMed2002

A naturally occurring mutation in the SLC21A6 gene causing impaired membrane localization of the hepatocyte uptake transporter.

The organic anion transporter SLC21A6 (also known as OATP2, OATP-C, or LST-1) is involved in the hepatocellular uptake of a variety of endogenous and xenobiotic substances and drugs. We analyzed 81 human liver samples by immunoblotting and found one with a strongly reduced amount of SLC21A6 protein suggesting mutations in the SLC21A6 gene. The SLC21A6 cDNA from this sample contained five base pair changes in one allele; three of the mutations resulted in amino acid substitutions designated SLC21A6-N130D, SLC21A6-P155T, and SLC21A6-L193R. The former two were polymorphisms (SLC21A6*1b and SLC21A6*4), whereas SLC21A6-L193R represents the first naturally occurring mutation identified in one allele of the SLC21A6 gene, which affects protein maturation and organic anion transport. We introduced each of the mutations into the SLC21A6 cDNA and established stably transfected MDCKII cells expressing the respective mutant SLC21A6 protein. Immunofluorescence microscopy and uptake measurements were used to study localization and transport properties of the mutated proteins. Both proteins carrying the polymorphisms were sorted to the lateral membrane like wild-type SLC21A6, but their transport properties for the substrates cholyltaurine and 17beta-glucuronosyl estradiol were altered. Importantly, most of the mutant protein SLC21A6-L193R was retained intracellularly, and this single amino acid exchange abolished transport function.

Amino Acid Sequence↗

PubMed2002

Early enteral supply of lactobacillus and fiber versus selective bowel decontamination: a controlled trial in liver transplant recipients.

BACKGROUND: Early enteral nutrition with solutions containing prebiotics (fiber) and probiotics (Lactobacillus) is suggested to reduce bacterial translocation and minimize the incidence of infections after liver transplantation. METHODS: In a prospective, randomized placebo-controlled trial consisting of 95 patients, we compared the incidence of postoperative infections and other complications after liver transplantation among three different groups, all supplied with early enteral nutrition: (a) standard formula plus selective bowel decontamination (SBD), (b) fiber-containing formula plus living Lactobacillus plantarum 299, and (c) fiber-containing formula plus heat-killed L plantarum 299. RESULTS: The groups were comparable regarding preoperative American Society of Anesthesiologists classification, Child-Pugh classification of cirrhosis, operative data, and degree of immunosuppression. The patients who received living lactobacilli plus fiber developed significantly fewer bacterial infections (13%) than the patients with SBD (48%). The incidence of infections was 34% in the group with inactivated lactobacilli and fiber. Cholangitis and pneumonia were the leading infections and enterococci the most commonly isolated bacteria. In the living Lactobacillus group, the mean duration of antibiotic therapy, the mean total hospital stay, and the stay on the intensive care unit were also shorter than in the groups with inactivated lactobacilli and fiber as well as with SBD. However, these differences did not reach statistical significance. CONCLUSIONS: Early enteral nutrition with fiber-containing solutions and living L plantarum 299 was well tolerated. It decreases markedly the rate of postoperative infections both in comparison with inactivated L plantarum 299 and significantly with SBD and a standard enteral nutrition formula. As it is a cheap and feasible alternative to SBD, further studies should evaluate whether this ecoimmunonutrition should be already started while patients are on the waiting list for transplantation.

Anti-Bacterial Agents↗

PubMed2002

Molecular mechanisms of polymorphic CYP3A7 expression in adult human liver and intestine.

Human CYP3A enzymes play a pivotal role in the metabolism of many drugs, and the variability of their expression among individuals may have a strong impact on the efficacy of drug treatment. However, the individual contributions of the four CYP3A genes to total CYP3A activity remain unclear. To elucidate the role of CYP3A7, we have studied its expression in human liver and intestine. In both organs, expression of CYP3A7 mRNA was polymorphic. The recently identified CYP3A7*1C allele was a consistent marker of increased CYP3A7 expression both in liver and intestine, whereas the CYP3A7*1B allele was associated with increased CYP3A7 expression only in liver. Because of the replacement of part of the CYP3A7 promoter by the corresponding region of CYP3A4, the CYP3A7*1C allele contains the proximal ER6 motif of CYP3A4. The pregnane X and constitutively activated receptors were shown to bind with higher affinity to CYP3A4-ER6 than to CYP3A7-ER6 motifs and transactivated only promoter constructs containing CYP3A4-ER6. Furthermore, we identified mutations in CYP3A7*1C in addition to the ER6 motif that were necessary only for activation by the constitutively activated receptor. We conclude that the presence of the ER6 motif of CYP3A4 mediates the high expression of CYP3A7 in subjects carrying CYP3A7*1C.

Adult↗

PubMed2002

Simultaneous splenectomy increases risk for opportunistic pneumonia in patients after liver transplantation.

Life threatening pneumonias after liver transplantation are often caused by opportunistic pathogens such as Legionella pneumophila, Pneumocystis carinii, Aspergillus species and cytomegalovirus (CMV). Due to the high incidence of morbidity and mortality caused by these pneumonias we reviewed 700 liver transplants for risk factors for the development of opportunistic pneumonia. Immunosuppression was commenced as either cyclosporin A- or tacrolimus-based protocols. In a subgroup of patients, splenectomy was performed simultaneously with liver transplantation ( n=57). Overall 60 opportunistic pneumonias occurred in 700 liver transplants. Using a stepwise logistic regression analysis, we found that OKT3 treatment and simultaneous splenectomy revealed a significantly increased risk for opportunistic pneumonia. Our study identified splenectomy as a major risk factor for the development of opportunistic pneumonia after liver transplantation. In these patients prophylactic protocols and early diagnosis may improve the long-term outcome.

Adolescent↗

PubMed2002

Discriminative quantification of cytochrome P4502D6 and 2D7/8 pseudogene expression by TaqMan real-time reverse transcriptase polymerase chain reaction.

The human drug oxidizing cytochrome P450, CYP2D6, is expressed at highly variable levels mainly due to a common genetic polymorphism which leads to the poor metabolizer phenotype in carriers of two nonfunctional alleles and to the extensive metabolizer phenotype in carriers of one or more functional alleles. Investigation of the role of CYP2D6 mRNA for expression and the possibility of using mRNA expression as a surrogate marker has been hampered by the presence of two pseudogenes, CYP2D7P and CYP2D8P. We therefore developed highly specific TaqMan real-time reverse transcriptase-PCR assays for the discriminative quantification of CYP2D6 and CYP2D7/8P transcripts. By in vitro transcription of plasmids containing the CYP2D6 cDNA or a hybrid CYP2D6/7 cDNA constructed by in vitro mutagenesis, authentic cRNAs were synthesized to be used for specificity testing and for absolute quantification. The method was used to determine CYP2D transcripts in a large number of human livers samples. CYP2D6 was not normally distributed with a median mRNA content of 3.2 transcripts per picogram of total RNA in all livers (range 0.32-14.8, N = 74). Expression in genetic poor metabolizers (1.81, N = 6) was significantly lower compared to extensive metabolizers (3.33, N = 68, P = 0.022). Similar expression levels were found for CYP2D7/8P (median 3.38 transcripts/pg, range 0.46-14.3), which were correlated to CYP2D6 mRNA (r(S) = 0.46, P < 0.0001) but did not depend on CYP2D6 genotype. These data demonstrate genotype-dependent mRNA expression for CYP2D6 and they emphasize the necessity of differentiating between the functional CYP2D6 and the CYP2D pseudogenes.

Base Sequence↗

PubMed2002

Results of end-to-end cavocavostomy during adult liver transplantation.

The results of end-to-end cavocavostomy during adult liver transplantation were analyzed with special regard to caval complications. In a series of 1000 liver transplants, we observed 17 patients who suffered from postoperative caval obstruction (6 patients) or caval stenosis (11 patients), for an incidence of 1.7%. Surgical therapy was performed in 10 patients (58.8%), and 5 patients required retransplantation (29.4%). Four patients died during the later postoperative course. Two fatalities were related to caval complications, resulting in a mortality rate of 11.8%. Our results indicate that end-to-end cavocavostomy is a safe technique for cavocaval anastomosis. For only a few exceptions, such as pediatric transplantation, reduced size livers, or size mismatch between donor and recipient, should alternative techniques such as end-to-side or side-to-side cavocavostomy be performed.

Adult↗

PubMed2002

Diagnostic value of peripheral blood T-cell activation and soluble IL-2 receptor for acute rejection in liver transplantation.

BACKGROUND: T-cells play an important role in the pathogenesis of rejection. Monitoring T-cells activation markers in peripheral blood may contribute to diagnosis of acute rejection after liver transplantation (LTX). METHODS: Lymphocyte subset distribution, expression of T-cell activation markers (flow cytometry), concentration of soluble (s) interleukin-2 receptor (IL-2R) (solid phase chemiluminescence immunoassay), and liver enzymes as well as bilirubin were prospectively tested in peripheral blood samples of LTX patients with (n=69) and without acute rejection (n=50). Acute rejection was assessed by standard criteria including liver biopsies. RESULTS: Intra-individual monitoring of immune parameters revealed an up-regulation of IL-2 receptor (CD25) expression on CD4 and CD8 T-cells together with increases in sIL-2R levels in patients with acute rejections. Measuring sIL-2R levels resulted in highest diagnostic efficiency (>85%). This level of diagnostic efficiency was not reached by any other marker tested. From all conventional markers of hepatocellular integrity and function, alkaline phosphatase reached the highest level of diagnostic efficiency with 70%. CONCLUSIONS: Monitoring of up-regulation of the IL-2/IL-2R pathway represents a useful tool for assessment of acute rejection after LTX.

Acute Disease↗

PubMed2002

DNA analysis of cholangiocarcinoma cells: prognostic and clinical importance.

INTRODUCTION: The clinical value of established prognostic factors seems to be limited since they fail to predict reliably survival of patients after resection of cholangiocarcinoma. DNA ploidy reflecting irregularities of chromosome number and content might be an alternative predictor. In this study, we evaluated the DNA ploidy as a prognostic factor for survival of patients after resection of cholangiocarcinoma. METHODS: This prospective study included 34 patients with cholangiocarcinoma which were surgically resected and followed up to death or more than 3 years. Tissue specimens were taken from the liver tissue immediately after resection and DNA ploidy determined. Survival was related to the type of DNA ploidy as well as to five established prognostic factors. RESULTS: Multivariate analysis revealed that in this study only DNA ploidy (P = 0.012) was significantly associated with prediction of survival. In contrast, neither tumor stage pT (P = 0.073) nor tumor grade pG (P = 0.154), resection margins R (P = 0.322), metastasis M (P = 0.060), lymph node stage pN (P = 0.209), age (P = 0.13) nor sex (P = 0.849) could significantly predict survival. Three-year survival was best for patients with diploid tumors (n = 6) of whom 75% survived more than 3 years. Poor prognostic signs associated with short term survival of less than 18 months were tumors classified as aneuploid (n = 17), large tumors pT4 (n = 8), metastasis pM1 (n = 11), undifferentiated tumors pG3 (n = 9) and non-tumor-free resection margins R2 (n = 14). The best predictor for poor prognosis was aneuploidy since it could identify more patients with a fatal outcome than other prognostic factors. DNA ploidy turned out to discriminate highly significant between diploid, polyploid and aneuploid tumors. DISCUSSION: The most accurate prognostic factor for survival of patients after resection of cholangiocarcinoma was DNA ploidy. Most patients suffering from a diploid tumor turned out to be long term survivors whereas aneuploid tumors indicated a poor prognosis with a rather short survival time of less than 18 months. We conclude that DNA ploidy is a valuable diagnostic tool for identifying subgroups of patients that are at higher risk for tumor progression.

Adult↗

PubMed2002

Psychosocial outcome of living donors after living donor liver transplantation: a pilot study.

In view of the scarcity of organ resources available for transplantation, living donor liver transplantation (LDLT) is gaining growing importance in the treatment of chronically terminal liver diseases. In the period between December 1999 and October 2000, 47 potential living liver donors were evaluated and 24 right hepatic lobes and two left lateral segments were transplanted at the Virchow-Klinikum of the Charité Hospital in Berlin. The present study looks into biomedical and psychosocial parameters of 23 donors before and 6 months after LDLT. Our aims were to investigate the development of psychosocial parameters after donation and the relationship between psychosocial findings and post-operative complications. Most donors showed an improved quality of life (QoL) after LDLT when compared with pre-operative results. Twenty-six percent of donors show high values for 'tiredness', 'fatigue' and 'limb pain' following donation. The post-operative complications had no influence on the psychosocial outcome. In this pilot study the resection of the right hepatic lobe amounts to a safe operation for donors and holds promise of a good psychosocial outcome for most donors, irrespective of donation-related complications. The pronounced complaints appears to indicate psychological tension and distress in some donors following donation.

Adult↗

PubMed2002

Impact of HLA-compatibilities in patients undergoing liver transplantation for HBV-cirrhosis.

Liver transplantation (OLT) for end-stage chronic hepatitis-B-virus (HBV) infection is frequently complicated by HBV recurrence. In the present study we investigated whether human leucocyte antigen (HLA)-matching influences the outcome after OLT. In a retrospective analysis we reviewed 84 recipients of liver transplants for end-stage HBV-cirrhosis and complete HLA-typing for outcome after OLT. Follow-up ranges from 1 to 110 months (median = 55.6 months). Immunosuppression consisted of Cyclosporin A (CsA)-based quadruple induction therapy or Tacrolimus-based induction protocols. Immunoprophylaxis with hepatitis B immunoglobulin was started at OLT and continued long-term. Actuarial 1- and 5-yr graft survival figures were 90.5 and 80.4%, respectively. Hepatitis-B recurrence was responsible for 15 of 20 (75%) graft failures. We observed a significantly improved graft survival in patients with more HLA-A, -B compatibilities (p = 0.02), whereas the degree of HLA-DR compatibilities did not influence the outcome. The occurrence of HBV-reinfection was significantly lower in HLA-A, -B matched grafts (p < 0.05). Additionally, graft survival was prolonged in patients with HBV-reinfection and 1 or 2 HLA-B compatibilities when compared with patients with HBV-reinfection and a complete HLA-B mismatch (p = 0.02). In conclusion, this retrospective analysis shows that more HLA-A, -B compatibilities seems to be associated with an improved graft survival in patients after OLT for end-stage HBV infection.

Graft Survival↗

PubMed2002

Extracorporeal liver perfusion as hepatic assist in acute liver failure: a review of world experience.

BACKGROUND: There are almost no prospective, controlled and randomized clinical trials comparing different approaches towards hepatic assist. In order to create a basis for comparing the value of the existing different hepatic assist methods this article offers a systematic review of the world experience with allogeneic or xenogeneic extracorporeal liver perfusion (ECLP). METHODS: An Internet-assisted search was conducted in the international literature published from 1964 to 2000. Only articles with a clear description of methodology and outcome of patients were included. For multivariate analysis of variance the general linear method (GLM) procedure was used. Differences within the groups were analyzed by chi-square test. Data of 198 patients were included into the statistical analysis for systematic review. RESULTS: The long-term survival rate (SVR) of these patients was 26%, thus not exceeding published data concerning SVR under standard intensive care. Age below 40 years (P<0.029), coma stage lower than III-IV (P<0.003), total perfusion time over 10 hours (P<0.024), hepatitis B as cause for acute liver failure (ALF) (P<0.05) as well as use of baboon and human livers (P<0.02) were identified as independent positive prognostic markers for improved survival. ECLP as bridging therapy to liver transplantation was successful in 12 of 14 patients. CONCLUSION: ECLP using pig livers did not surpass the success of conventional intensive care treatment. An additional effect of transgenic expression of human regulators of complement regulation in porcine livers has not yet been proven. ECLP with human livers not suitable for liver transplantation might prove effective and practicable for temporary hepatic support. Bridging to liver transplantation by long-term ECLP using porcine and human livers appears to have comparable efficacy as bioartificial support methods.

Acute Disease↗

PubMed2002

Accumulation of crystal deposits in abdominal organs following perfusion with defrosted University of Wisconsin solutions.

Previous studies reported on both visible and invisible particles in University of Wisconsin (UW) solutions. Those particles originated from components of the bags. In recent clinical observations we noticed macroscopically visible, indissoluble particles in UW bags reaching subzero temperatures during transportation of organs and preservation solutions. In an experimental model we examined whether those particles could be detected following perfusion of abdominal organs with established perfusion solutions. UW-, HTK- or physiological saline solutions reached -3 +/- 0.5 degrees C under conditions frequently applied during transportation. UW solutions demonstrated the accumulation of visible, indissoluble crystals and were subsequently used for the perfusion of abdominal organs in LEW rats. After perfusion with UW solutions stored at freezing temperatures, crystals were detected in all abdominal organs localized in and around vessels, bile ducts, glomeruli and in the interstitium of harvested livers, kidneys and pancreas. By spectroscopy, we were able to characterize crystals as adenosine. A 40-microm pore-size filter eliminated crystals from UW solutions. Crystals were absent in organs perfused with HTK- or saline solutions kept at subzero conditions. UW solutions can reach subzero temperatures under commonly used transportation conditions. Under these conditions, visible crystals accumulate and can be detected in abdominal organs of an experimental system.

Adenosine↗

PubMed2002

Adenovirus-mediated gene transfer of P16INK4/CDKN2 into bax-negative colon cancer cells induces apoptosis and tumor regression in vivo.

The tumor-suppressor gene p16INK4/CDKN2 (p16) is a cyclin-dependent kinase (cdk) inhibitor and important cell cycle regulator. Here, we show that adenovirus-mediated gene transfer of p16 (AdCMV.p16) into colon cancer cells induces uncoupling of S phase and mitosis and subsequently apoptosis. Flow cytometric analysis revealed that cells infected with AdCMV.p16 showed an initial G2-like arrest followed by S phase without intervening mitosis (DNA >4N). Using microscopic analysis, deformed polyploid cells were detectable only in cells infected with AdCMV.p16 but not in control-infected cells. Subsequently, AdCMV.p16-infected polyploid cells underwent apoptosis, as assessed by AnnexinV staining and DNA fragmentation, suggesting that cell cycle dysregulation is upstream of the onset of apoptosis. Treatment of mice with subcutaneously transplanted tumors of colorectal cancer cells with AdCMV.p16 but not AdCMV.p53 resulted in significantly reduced tumor volume and prolonged survival. Using an orthotopic model of liver metastasis, we observed both reduced local tumor growth and secondary intrahepatic metastasis after AdCMV.p16 treatment. Importantly, induction of apoptosis in vitro and reduction of tumor growth in vivo by p16 was p53- as well as bax-independent because identical results were obtained using cancer cells, either wild type or mutant for p53 or bax. The studies suggest that an AdCMV.p16-based treatment may be especially effective in patients with bax-negative colon cancer where overexpression of p53 appears not to be of therapeutic value.

Adenoviridae↗

PubMed2002

The influence of CYP2B6, CYP2C9 and CYP2D6 genotypes on the formation of the potent antioestrogen Z-4-hydroxy-tamoxifen in human liver.

AIMS: To investigate in a large panel of 50 human liver samples the contribution of CYP2C9, CYP2D6, and CYP3A4 to the overall formation of the potent antioestrogen Z-4-hydroxy-tamoxifen, and how various genotypes affect its formation from tamoxifen. METHODS: The formation of Z-4-hydroxy-tamoxifen from 10 microm tamoxifen was studied in human liver microsomes (n=50), characterized for CYP2B6, CYP2C9, CYP2D6 and CYP3A4 expression, and CYP2B6, CYP2C9 and CYP2D6 genotype. The effect of chemical and monoclonal antibody inhibitors, and the formation in supersomes expressing recombinant CYP isoforms was also investigated. Z-4-hydroxy-tamoxifen was quantified using LC-MS analysis. RESULTS: Z-4-hydroxy-tamoxifen was formed by supersomes expressing CYP2B6, CYP2C9, CYP2C19 and CYP2D6, but not CYP3A4. In agreement with these data, the mean formation of Z-4-hydroxy-tamoxifen was inhibited 49% by sulphaphenazole (P=0.001), 38% by quinidine (P<0.05) and 13% by monoclonal antibody against CYP2B6 (MAB-2B6, P<0.05). Furthermore, Z-4-hydroxy-tamoxifen formation significantly correlated with both CYP2C9 expression (r(s)=0.256, P<0.05) and CYP2D6 expression (r(s)=0.309, P<0.05). Genotypes of CYP2D6, CYP2B6 and CYP2C9 had an effect on metabolite formation in such a way that samples with two nonfunctional CYP2D6, or two variant CYP2C9 or CYP2B6 alleles, showed lower enzyme activity compared with those with two functional or wild-type alleles, (5.0 vs 9.9 pmol mg(-1) protein min(-1), P=0.046, 5.1 vs 9.9 pmol mg(-1) protein min(-1), P=0.053, and 6.8 vs 9.4 pmol mg(-1) protein min(-1), P=0.054, respectively). CYP2D6 and CYP2C9 contribute on average 45 and 46%, respectively, to the overall formation of Z-4-hydroxy-tamoxifen. CONCLUSIONS: CYP2B6, CYP2C9 and CYP2D6 genotypes all affected Z-4-hydroxy-tamoxifen formation and can predict individual ability to catalyse this reaction.

Adolescent↗