[Knowledge, attitude and opinion of patients regarding the new German legislation on advance care planning : Results of a survey in a department of general internal medicine]. / Wissen, Haltung und Meinung von Patienten zum neuen Patientenverfügungsgesetz : Ergebnisse einer Umfrage in einer allgemeininternistischen Abteilung.

BACKGROUND: In September 2009 a new legislation for advance care planning was introduced in Germany with the important characteristics of bindingness and unlimited validity for individual directives. Knowledge regarding this act and the attitude towards its characteristics among patients is unclear. AIM OF THIS STUDY: Analysis of knowledge, attitude and opinion of patients in a general internal medical department regarding advance care planning in general and the recent German legislation. METHODS: A total of 200 consecutive patients in an internal medicine ward were interviewed with the help of a questionnaire regarding their attitude to and knowledge on advance care planning in general and the current legislation. RESULTS: Approximately 40 % of the patients had issued some form of directive (either advance care directive or health care proxy) and only 7.5 % were advised by their physicians to make an advance directive. Patients with no directive were not willing to deal with dying and death, were not well-informed about directives or assumed that relatives or physicians would make an appropriate decision. Characteristics of the new legislation were controversially assessed; only 21 % of the patients wished to have a literal implementation of their directive. Regarding the content of an advance directive, more than 80 % of the patients voted for pain control in the palliative setting. CONCLUSION: The proportion of patients with a directive regarding advance care planning is only slowly increasing. Many patients are not well-informed, do not want to deal with dying or would like to delegate decisions to relatives and physicians. The present characteristics of the German legislation are controversially assessed and often do not represent the wishes of the patients.

Is there a role for capsule endoscopy in the staging work-up of patients with gastric marginal zone B-cell lymphoma of MALT?

INTRODUCTION: In earlier studies, involvement of the small intestine was reported in patients with gastrointestinal lymphoma. Prospective data on the involvement of the small intestine in patients suffering from gastric extranodal MZBCL of MALT do not exist so far. In this study, we investigated the frequency of the involvement of the small intestine and the role of capsule endoscopy in patients with gastrointestinal extranodal MZBCL of MALT and of follicular lymphoma. PATIENTS AND METHODS: 40 consecutive patients with gastrointestinal extranodal MZBCL of MALT (26 men, 14 women, aged 27 - 80 years), and 7 patients with known follicular lymphoma of the small intestine (5 men, 2 women, aged 34 - 63 years) underwent capsule endoscopy. RESULTS: Involvement of the small intestine was identified by capsule endoscopy in all 7 patients with known follicular lymphoma of the small intestine. In 6 of 40 patients with gastric extranodal MZBCL of MALT abnormal findings could be observed, three of these findings indicative for lymphoma involvement of the small intestine. However, in each of these 3 cases, intestinal involvement had been already diagnosed by conventional GI endoscopy before capsule endoscopy. CONCLUSIONS: Capsule endoscopy is able to detect involvement of the small intestine in patients with gastrointestinal lymphoma. However, involvement of the small intestine seems to be rare in patients with gastric extranodal MZBCL of MALT. In summary, routine diagnostic work-up of the small intestine, e. g. by capsule endoscopy seems unnecessary because of the rare involvement of the small intestine and an excellent long-term outcome irrespective of a possible intestinal manifestation.

Raising awareness about chronic intestinal pseudo-obstruction (CIPO): a case report showing CIPO as initial manifestation of atypical seronegative systemic sclerosis.

Only few case studies address pseudo-obstruction, a disorder - which often frustrates clinicians and patients due to an unclear diagnosis and limited therapeutic options. Thus, the aim of this paper is to investigate a relevant case concerning a patient presenting with symptoms of acquired chronic intestinal pseudo-obstruction (CIPO). After one year of extensive diagnostic tests and unsuccessful treatment with prokinetics, the patient underwent a subtotal ileocolectomy. The histology of the intestinal specimen revealed continuous atrophy and fibrosis mainly within the circular, inner muscle layer of muscularis propria of the ileum and colon. Even though serum markers were lacking, a subsequent skin biopsy showed signs of scleroderma supporting an initial diagnosis of intestinal involvement in systemic sclerosis. Despite treatment with steroids and methotrexate, the increasingly emaciated patient died. In conclusion, there is a bias against the publishing of pseudo-obstruction studies, in particular, due to the obscure underlying causes. To raise awareness of this problem, we call for clinicians to systematically generate comprehensive data about patients presenting these symptoms.

[Severe hepatitis and subacute liver failure with "fast track" cirrhosis in an elderly lady]. / Schwere Hepatopathie und subakutes Leberversagen mit "Fast-track"-Leberzirrhose bei älterer Patientin.

We report the case of a 74-year-old lady who presented at our clinic with icterus and cholestatic hepatitis. For atrial fibrillation she had been prescribed a medication with phenprocoumone. After ruling out viral, autoimmune, and metabolic causes of hepatitis, we performed a liver biopsy which led to the diagnosis of phenprocoumone-related liver damage. The patient was discharged without phenprocoumone and completely compensated liver function. Five weeks later she returned to the hospital with encephalopathy, ascites, coagulopathy, varices, and signs of cirrhosis in abdominal ultrasound. In spite of treatment with steroids, the patient died of subacute liver failure several weeks later. This case illustrates the occasionally poor course of toxic hepatitis even after discontinuation of the responsible medication, potential treatment options are discussed.

[Role of endoscopic ultrasound in gastrointestinal lymphomas]. / Stellenwert des endoskopischen Ultraschalls bei gastrointestinalen Lymphomen.

The majority of gastrointestinal lymphomas belongs to the group of the MALT (mucosa-associated lymphoid type) lymphomas arising in the stomach, therefore rendering them accessible to endoscopy. Staging currently follows the modified Ann Arbor classification but most likely in the future, the TNM-based Paris staging system will be applied due to its detailed description of the local spread as well as the extraintestinal dissemination. For assessment of gut wall infiltration and local lymphonodular involvement, endoscopic ultrasound currently represents the standard procedure and is an essential diagnostic tool regarding locoregional staging. Additionally, the method confers a high prognostic value regarding treatment response in MALT lymphoma. In endoscopic ultrasound stage EI 1, Helicobacter pylori eradication leads in 70 - 100 % to a complete response. However, the value of endoscopic ultrasound in the follow-up of lymphomas after chemotherapy remains elusive and controversial. There is no clear correlation between histologically proven residual disease and endosonographic results. Thus, so far, endoscopic ultrasound will not replace bioptic surveillance after MALT lymphoma treatment.

[Severe refractory pulmonary hypertension after liver transplantation for hepatitis C liver cirrhosis]. / Therapierefraktäre schwere pulmonal-arterielle Hypertonie nach Lebertransplantation bei HCV-Leberzirrhose.

BACKGROUND: We report the case of a 43-year-old male with liver cirrhosis based on a chronically active hepatitis C. CASE REPORT: Before liver transplantation right-ventricular pressure values of 36 mmHg (+ central venous pressure) were measured whereas, after transplantation, he developed severe pulmonary hypertension with pressure values up to 90 mmHg. These elevated pressure values correlated inversely with graft function. Given the diagnosis of portopulmonary hypertension, we initiated treatment with intravenous epoprostenol and inhalative iloprost but both treatments were not tolerated because of systemic side effects. A combined heart-lung transplantation was considered but the patient died from insufficient cardiac function. CONCLUSIONS: The case report discusses the present diagnostic and therapeutic state of the art in portopulmonary hypertension and reveals basic problems of the present screening strategy.

[Extrahepatic manifestations of chronic liver diseases]. / Extrahepatische Manifestationen chronischer Lebererkrankungen.

Chronic liver diseases are commonly associated with extrahepatic disease manifestations. Liver cirrhosis, the end stage of chronic liver diseases of different etiologies, can result in severe neurological, renal and pulmonary complications. Hepatic encephalopathy plays an important socio-economic role, since it affects daily functioning and fitness to drive. During the clinical course of chronic viral hepatitis, many patients develop extrahepatic disease manifestations, which lead to significant morbidity and mortality. In particular, mixed cryoglobulinemia, membranoproliferative glomerulonephritis and polyarteriitis nodosa are strongly associated with chronic viral hepatitis. Most extrahepatic manifestations are due to immunological and lymphoproliferative pathomechanisms. Knowledge of extrahepatic disease manifestations is important for adequate medical care and risk assessment of patients with chronic liver diseases by insurance companies.

Cutaneous mucinosis and skin necrosis complicates interferon alfacon-1 (consensus interferon) treatment of chronic hepatitis C.

A 59-year-old Caucasian suffering from chronic hepatitis C started daily subcutaneous self-injections of interferon alfacon-1 (consensus interferon) according to the protocol of a randomised multicentre study. At week 10, he developed painful erythematous lesions at two injection sites. Consensus interferon dosage was reduced, and eventually, the lesions healed with small areas of scarring due to central necrosis. At week 51, again large areas of erythematous thickened skin arose at two other injection sites followed by substantial ulceration and central necrosis. Skin biopsy revealed excessive dermal mucin deposition so that cutaneous mucinosis was diagnosed. After 3-6 months, the lesions healed with central scarring. Due to a persistently negative HCV-PCR from serum (from week 12 onwards), consensus interferon treatment was not stopped but continued until week 60 according to the study protocol. - Cutaneous mucinosis has not been previously reported to complicate treatment with consensus interferon in patients with chronic hepatitis C and should therefore be added to the list of dermatological side-effects associated with interferon alfacon-1 therapy.

Influence of biliary cirrhosis on the detoxification and elimination of a food derived carcinogen.

BACKGROUND AND AIMS: The liver is the central organ for the detoxification of numerous xenobiotics, including carcinogens. We studied the influence of cholestasis and biliary cirrhosis on the detoxification, elimination, and tissue distribution of a model compound and food derived carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). METHODS: Wistar rats were injected with (14)C-PhIP into the portal vein one or six weeks after common bile duct ligation (CBDL). Bile flow was reconstituted, bile and urine were collected over 120 minutes, and metabolites were analysed using high performance liquid chromatograpy. Total tissue radioactivity levels in several organs as well as tissue bound (ethanol insoluble tissue fraction) radioactivity levels were determined. RESULTS: Significant downregulation of the transport proteins multidrug resistance associated protein 2 and breast cancer resistance protein was observed in biliary cirrhosis. Biliary excretion of radioactivity was significantly reduced in cholestasis and biliary cirrhosis compared with controls (15 (2.9)% and 3.2 (1)% of the dose v 36.5 (2)%, respectively). Phase II metabolism was severely reduced in cirrhotic rats, resulting in a twofold increase in tissue radioactivity levels in the liver, kidney, and colon. Biliary cirrhosis increased tissue binding of reactive metabolites, as expressed in cpm/100 mg tissue in the liver and the colon (3267 (1218) v 1191 (429) in the liver, 3044 (1913) v 453 (253) in the colon). CONCLUSIONS: Biliary cirrhosis induced by CBDL causes impaired metabolism and elimination of PhIP, and leads to higher tissue levels of potentially genotoxic metabolites in the liver and colon of rats. These data may explain the increased incidence of hepatic and extrahepatic cancers in cholestasis and liver cirrhosis.

[Gastrointestinal stromal tumors: a broad clinical spectrum from incidental -discovery to acute gastrointestinal bleeding]. / Gastrointestinale Stromatumoren (GIST): variable klinische Manifestationen vom Zufallsbefund bis zur akuten gastrointestinalen Blutung.

Three cases of gastrointestinal stromal tumors (GIST) are reported as typical examples of the broad clinical spectrum in which these rare tumors can be detected. The first case describes an 82-year-old patient with a hemorrhagic shock due to upper gastrointestinal bleeding from a GIST of the stomach. GIST most frequently present with either gastrointestinal bleeding, abdominal pain or a detectable mass on physical examination or by ultrasound imaging. Clinically asymptomatic tumor growth also occurs as demonstrated by the second case of a 44-year-old -woman with an incidental finding of GIST during surgery of the esophagus. The cases are used to discuss the consequences for therapy and prognosis resulting from the heterogeneity of this tumor entity; the relevant immunohistochemical markers used to distinguish between various tumor subtypes of gastrointestinal mesenchymal tumors (GIMT) are listed. Since gastrointestinal stromal tumors (GIST) represent the most common subgroup of GIMT, we focus on the clinicopathological prognostic factors of GIST. The third case of a 40-year-old patient with a malignant GIST recurrence after surgery and exhibiting secondary resistance after one year of successful therapy with the receptor tyrosine kinase inhibitor imatinib (Gleevec), antagonizing pathogenetically relevant constitutive c-KIT activation, illustrates the potential and limitations of the only effective drug treatment for advanced GIST.

ABC of oral bioavailability: transporters as gatekeepers in the gut.

MDR1 (ABCB1), MRP2 (ABCC2), and BCRP (ABCG2) are members of the family of ATP binding cassette (ABC) transporters. These are plasma membrane transporters that are expressed in various organs. The role of MDR1 and MRP2 in the hepatobiliary system is well defined; both contribute to bile formation by transport of drugs, toxins, and waste products across the canalicular membrane. As they transport exogenous and endogenous substances, they reduce the body load of potentially harmful compounds. The role of ABCG2, which is also expressed in the canalicular membrane of hepatocytes, has not yet been fully characterised. All three proteins are also expressed in the apical membrane of enterocytes where they probably control oral availability of many substances. This important "gatekeeper" function of ABC transporters has been recognised recently and is currently under further investigation. Expression and activity of these transporters in the gut may differ between individuals, due to genetic polymorphisms or pathological conditions. This will lead to individual differences in bioavailability of different drugs, toxins, and (food derived) carcinogens. Recent information on substrates, transport mechanisms, function, and regulation of expression of MDR1, MRP2, and BCRP in different species is summarised in this review.

Constitutive rat multidrug-resistance protein 2 gene transcription is down-regulated by Y-box protein 1.

BACKGROUND/AIMS: Molecular mechanisms underlying transcriptional rat multidrug-resistance protein 2 (Mrp2, Abcc2) gene regulation are mostly unclear. Given the presence of putative binding sites for the Y-box binding protein YB-1 in the regulatory sequence, its trans-regulatory influence was analyzed. METHODS: Reporter assays in HepG2 cells with various Mrp2 deletion constructs in the absence and presence of co-transfected YB-1 were performed. DNA binding studies with recombinant YB-1 protein and nuclear extracts obtained from HepG2 cells and rat liver tissue were carried out. RESULTS: The minimal promoter sequence was confined to the proximal 186 bp. A YB-1 responsive element, Mrp2 YRE-1, was mapped at -186/-157, which exhibits specific YB-1 binding. YB-1 acts as a potent repressor of Mrp2 promoter activity in vitro. CONCLUSIONS: Constitutive Mrp2 gene expression is conferred through the proximal -186 bp. YB-1 acts as a repressor in vitro by specific binding to a defined element in the proximal promoter sequence.

Activity and cellular origin of gelatinases in patients with colon and rectal carcinoma differential activity of matrix metalloproteinase-9.

BACKGROUND: Expression and enzymatic activity of gelatinases were examined in biopsy specimens from patients with colon and rectal neoplasms. The objective of this study was to determine whether the activity of these enzymes is altered between tumor areas compared with areas of noninvolved, normal mucosa and between colon and rectal carcinoma. METHODS: Matrix metalloproteinase (MMP) production was analyzed by Western immunoblot analysis and gelatin zymography. mRNA was determined by quantitative, real-time polymerase chain reaction analysis. RESULTS: Patients with colon carcinoma (n = 20 patients) showed a significant increase in levels of MMP-9 (92 kDa and 88 kDa) and MMP-2 (72 kDa and 62 kDa) in tumor areas compared with noninvolved regions. In contrast, patients with rectal carcinoma (n = 10 patients) had revealed the same high activity of MMP-9 in tumor regions and corresponding healthy tissue. Confirming activity measurements, in colon tumors, but not in rectal tumors, there was significant up-regulation of MMP-9 transcription compared with healthy tissue in the same patients. There were no significant changes in the tissue inhibitor of metalloproteinase-1 protein when colon and rectal tumor tissues were compared with the corresponding noninvolved regions. Cell culture experiments revealed fibroblasts as the cellular origin of MMPs. The findings showed that the secretion and activation of gelatinases depend on soluble factors secreted by tumor cells and are influenced by extracellular matrix components. CONCLUSIONS: This is the first report showing differences in MMP-9 activity between rectal carcinoma and colon carcinoma. Previous results indicating an active involvement of stromal cells in the generation of MMPs during tumor invasion are extended. Because the abundance of gelatinases increases in colorectal carcinoma, inhibitors of these proteases may be of therapeutic value.

[Heterophile antibodies, lack of communication and the diagnostic dilemma]. / Heterophile Antikörper, fehlende Kommunikation und das diagnostische Dilemma.

BACKGROUND: Heterophilic antibodies represent a great danger to clinical care by producing false-positive values for certain markers. Too large confidence in specificity of laboratory markers together with lack of communication between clinicians and clinical chemists may lead to unnecessary interventional diagnostic and therapeutic procedures. The prevalence of heterophilic antibodies is probably much higher than assumed up till now and several markers can be affected. AIM: In this review for clinicians, we explain formation of heterophilic antibodies, mechanisms of interference and present clinical data about affected markers and "side effects" from the literature. Furthermore we discuss possible alternatives and measures against this phenomenon. We consider broad awareness of this problem among clinicians the most important action to avoid further harm to patients.

Role of MRP2 and GSH in intrahepatic cycling of toxins.

MRP2 is a canalicular transporter in hepatocytes mediating the transport of a wide spectrum of amphipathic compounds. This includes organic anions but also compounds complexed with GSH as, e.g. alpha-naphthylisothiocyanate (ANIT) and arsenite. These reversible complexes may fall apart in bile after MRP2-mediated transport, which induces high concentrations of the toxic compound in the biliary tree. To further investigate the role of MRP2 in transport and toxicity of both compounds, we conducted experiments in transduced polarized epithelial cells and in vivo, using the Mrp2-deficient TR(-) rat as a model. Our results show, that in MRP2-transduced MDCK II cells both compounds induce disproportionally strong apical GSH secretion. This induction of GSH secretion was not observed in the parent cells lacking MRP2 expression. This indicated that after transport via MRP2 both complexes released GSH upon which the compound could re-enter the cells. The resulting cycling of both toxins led to concentration dependent GSH depletion of the cells. To further test our hypothesis we administered arsenite (12.5 micromol absolute i.v.) to Wistar and Mrp2-deficient TR(-) rats and collected bile. While both arsenite and GSH secretion were absent in TR(-) rats, the total secretion of arsenite into Wistar bile (2.91 micromol) was accompanied by a excess secretion of 24 micromol GSH, indicating that arsenite undergoes multiple cycles of GSH complexation. We also administered ANIT to both animal models and could show that TR(-) rats are protected from ANIT induced cholestasis. This indicates that Mrp2-mediated biliary secretion of GS-ANIT is a prerequisite for development of cholestasis in rats. We hypothesize that the toxic parent compound ANIT is regenerated in the biliary tree where it can exert its toxic properties on bile duct epithelial cells.

Mrp2-deficiency in the rat impairs biliary and intestinal excretion and influences metabolism and disposition of the food-derived carcinogen 2-amino-1-methyl-6-phenylimidazo.

While metabolism of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), the most abundant food-derived heterocyclic amine and carcinogen, has been studied extensively in several species, transport of this compound and its metabolites has not been defined yet. Therefore we studied metabolism and disposition of PhIP in Wistar and Mrp2-deficient TR(-) rats to determine the role of Mrp2 in the defence against this compound. In the first 2 h after intravenous dosing, total excretion of PhIP and its metabolites in bile was > 4-fold reduced in TR(-) rats compared with Wistar rats, while excretion in the urine of the TR(-) rat was 1.8-fold higher. This difference was the result of an almost complete absence of secretion of glucuronidated metabolites but also a reduced level of secretion of unchanged PhIP into bile of the TR(-) rat. Direct intestinal excretion of unmetabolized PhIP was 3-fold higher in Wistar versus TR(-) rats. As a consequence, PhIP tissue levels in the liver were 1.7-fold higher in TR(-) rats, and tissue binding of PhIP, determined after ethanol extraction, was elevated by a similar magnitude. Mrp2-mediated transport of the parent compound PhIP is glutathione (GSH)-dependent, because GSH depletion by L-buthionine-[S,R]-sulfoximine (BSO) treatment in Wistar rats reduced intestinal secretion to the same level as that in TR(-) rats. TR(-) rats produced less glucuronides and 4'-OH-PhIP in the 2 h following PhIP administration. We conclude that Mrp2 protects against the carcinogen PhIP by biliary excretion of the parent compound and all major phase-II metabolites, but, more importantly, also by direct extrusion of the parent compound from the gut mucosa.

Increased bioavailability of the food-derived carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in MRP2-deficient rats.

MRP2 is an apical transporter expressed in hepatocytes and the epithelial cells of the small intestine and kidney proximal tubule. It extrudes organic anions, conjugated compounds, and some uncharged amphipaths. We studied the transport of an abundant food-derived carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in vitro, using an MRP2 transfected epithelial cell line (MDCK II) and intestinal explants from Wistar and MRP2-deficient TR(-) rats in Ussing chambers. In the experiments with the transfected cell line, we could demonstrate more than 3-fold higher transport from basolateral to apical than vice versa, whereas the transport in the parent cell line was equal in both directions. These results were confirmed in studies using isolated pieces of small intestine from Wistar and TR(-) rats in the Ussing chamber. Subsequent in vivo experiments demonstrated that after oral administration, absorption of PhIP was 2-fold higher in the TR(-) rat than in the Wistar rat. Consequently, PhIP tissue levels in several organs (liver, kidney, lung, and colon) were 1.7- to 4-fold higher 48 h after oral administration. MRP2 mediated transport of unchanged PhIP probably involves intracellular GSH, because GSH depletion by BSO-treatment in Wistar rats reduced intestinal secretion in the Ussing chamber to the same level as in TR(-) rats. In accordance, BSO treatment increased oral bioavailability in intact Wistar rats. This study shows for the first time that MRP2-mediated extrusion reduces oral bioavailability of a xenobiotic and protects against an abundant food-derived carcinogen.

[Solitary fibrous thoracic wall tumor. Progression with percutaneous radiotherapy]. / Solitärer fibröser Thoraxwandtumor. Progredienz unter perkutaner Radiatio.

HISTORY AND CLINICAL FINDINGS: A 81-year-old patient free of pain was referred to the university hospital for further evaluation and therapy of tumour masses in the right thorax. Clinical examination revealed dullness to percussion and reduced breathing in the right lower lung. INVESTIGATIONS: Computed tomography showed an enlarged solid tumour mass attached to the thoracic cavity and pleural effusion on the right side. Quantification of pulmonary perfusion presented significant defects in the right upper and middle lobe. DIAGNOSIS, TREATMENT AND COURSE: The pulmonary masses were biopsied under CT-guidance. Biopsy and immunohistochemical findings proved a malignant solitary fibrous tumour of the chest wall, a mesenchymal tumour of its own entity. Because of pain in the right arm and because of missing other reliable therapeutic options a palliative irradiation was performed. The tumour did increase in size due to radiotherapy and a severe right ventricular heart failure occurred. The patient died 5 months after diagnosis has been made. Autopsy revealed a transition of tumour cells to sarcomatic growth. CONCLUSION: In our case we conclude an accelerated progression of the solitary fibrous chest wall tumour in the course of irradiation. Whether the development of sarcomatic growth occurred as a result of radiotherapy remains speculative.

Lack of UGT1 isoforms in Gunn rats changes metabolic ratio and facilitates excretion of the food-derived carcinogen 2-amino-1-methyl-6-phenylimidazo.

UDP-glucuronosyltransferases (UGTs) play an important role in detoxification of endo- and xenobiotics. Deficiencies of these enzymes can have serious consequences, for example, in Crigler-Najjar disease Type I. Recently it was shown that the activated form of the abundant food-derived carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is glucuronidated mainly by UGT1 isoforms. Therefore UGT1 deficiency may have an important impact on metabolism and excretion of PhIP in the body and consequently for the susceptibility toward carcinogenic effects through PhIP. To test this hypothesis we investigated fate and distribution of PhIP in the UGT1-deficient Gunn rat. In 2 h after intravenous injection of PhIP, Gunn rats excreted significantly more PhIP and metabolites than control animals, which were age- and weight-matched Wistar rats. In bile, both glucuronides of N-OH-PhIP were reduced but, in urine, only the N3-glucuronide was reduced while the N2-glucuronide was elevated. The metabolic pathway ratio between 4'-hydroxylation and N-hydroxylation was dramatically changed in the Gunn rat (five times higher in bile and doubled in urine, resulting in a four times higher ratio in total), mostly because of the doubled amount of 4'-PhIP-sulfate in Gunn rats compared to Wistar rats. Tissue levels of PhIP and metabolites were significantly lower in liver and colon of the Gunn rats. We conclude that, in Gunn rats, PhIP is alternatively metabolized through UGT2B enzymes and sulfotransferases, which adds another clue to the potential importance of sulfotransferases in detoxification of PhIP.