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P L Jansen

Publications and source records attributed to P L Jansen.

At least 19 recordsLinked to original sources
PubMed2001

Increased cancer risk after liver transplantation: a population-based study.

BACKGROUND/AIMS: Development of de novo malignancies emerges as a serious long term complication after liver transplantation. METHODS: We reviewed the medical records of 174 adult one-year survivors for de novo malignancies. The observed cancer rates were compared with the expected cancer rates in the Dutch population. RESULTS: Twenty-one of the 174 patients developed 23 malignancies (12%). Skin and lip cancer accounted for 12 of the 23 malignancies (52%). Only one patient had a B-cell lymphoma. The cumulative risk for de novo malignancy was 6, 20, and 55% at 5, 10, and 15 years after transplantation, respectively. The overall relative risk (RR) as compared with the general population was 4.3 (95% confidence interval 2.4-7.1). Significantly increased RRs were observed for non-melanoma skin cancer (RR 70.0), non-skin solid cancer (RR 2.7), renal cell cancer (RR 30.0), and colon cancer (RR 12.5). Multivariate analysis showed that an age > 40 years and pretransplant use of immunosuppression were significant risk factors. CONCLUSIONS: An increased risk of cancer exists after liver transplantation, for both for skin/lip cancer, and other solid tumors. Older age and the use of immunosuppression are risk factors.

Adult↗
PubMed2001

Induction of Mdr1b expression by tumor necrosis factor-alpha in rat liver cells is independent of p53 but requires NF-kappaB signaling.

The multidrug resistance protein Mdr1b in rats is up-regulated during liver regeneration after partial hepatectomy or after endotoxin treatment. We hypothesize that up-regulation of Mdr1b in these models is TNF-alpha-dependent. The mechanism of Mdr1b activation by TNF-alpha is unknown as TNF-alpha can signal through various pathways, including NF-kappaB and p53, transcription factors for which binding sites in the Mdr1b promoter have been identified. We aimed to elucidate the mechanism of up-regulation of Mdr1b by TNF-alpha. We selectively used constructs expressing dominant negative Fas-associated death domain protein (FADD), TNF receptor associated factor-2 (TRAF2) or IkappaB to inhibit pathways downstream of the TNF receptor. Further, the proteasome inhibitor MG-132 was used, which prevents the breakdown of IkappaB. We show a critical role for NF-kappaB in activation of Mdr1b gene expression both in primary rat hepatocytes and in rat hepatoma H-4-II-E cells. Because p53 is up-regulated by TNF-alpha in an NF-kappaB-dependent manner and the Mdr1b promoter contains a p53 binding site, we used liver cells expressing a dominant negative p53 to show that TNF-alpha up-regulation of Mdr1b is independent of functional p53. Using transient transfection assays, we show that Mdr1b up-regulation correlates with activation of the promoter. Mutation of the NF-kappaB site in the Mdr1b promoter prevents its induction by TNF-alpha. In conclusion our results show that activation of the rat Mdr1b gene by TNF-alpha is a result of NF-kappaB signaling and independent of p53.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2001

Hyperlipidemia and atherosclerosis associated with liver disease in ferrochelatase-deficient mice.

Erythropoietic protoporphyria (EPP) is an inherited disorder of heme synthesis caused by deficiency of the mitochondrial enzyme ferrochelatase. EPP in humans is associated with liver disease, hypertriglyceridemia, and a low level of high density lipoprotein (HDL) cholesterol. To explore consequences of ferrochelatase deficiency in lipid metabolism, we have analyzed hepatic lipid content and plasma lipoprotein levels in chow-fed BALB/c mice homozygous ( fch/fch) or heterozygous ( fch/1) for a point mutation in the ferrochelatase gene and in wild-type controls (1/1). Livers of fch/fch mice show bile duct proliferation and biliary fibrosis, but bile formation is not impaired. The free cholesterol content of fch/fch livers is significantly increased when compared with fch/1 and 1/1 livers. Plasma cholesterol in fch/fch mice (9.9 +/- 6.4 mM) is elevated when compared with fch/1 and 1/1 mice (2.9 +/- 0.2 and 2.5 +/- 0.3 mM, respectively), because of an increased cholesterol content in the very low density lipoprotein-sized fractions, whereas HDL cholesterol is reduced. The ratio of cholesteryl ester to free cholesterol is 4.3 +/- 0.6, 3.3 +/- 0.3, and 0.3 +/- 0.1 in the plasma of 1/1, fch/1, and fch/fch mice, respectively. The latter is not due to reduced lecithin:cholesterol acyltransferase activity in plasma of fch/fch mice but to the presence of lipoprotein-X (Lp-X), a particle composed of bile-type lipids usually seen only in cholestatic conditions. Expression of mdr2, essential for biliary phospholipid/cholesterol secretion, is increased in fch/fch livers. In spite of this, biliary phospholipid/cholesterol secretion is reduced relative to that of bile salts. It is postulated that an inability of bile salts to stimulate lipid secretion adequately leads to formation of Lp-X in this noncholestatic condition. Distinct atherosclerotic lesions were found in aged fch/fch mice.Thus, ferrochelatase deficiency in mice leads to liver disease associated with altered hepatic lipid metabolism, a characteristic hyperlipidemia, and development of atherosclerosis.-Bloks, V. W., T. Plösch, H. van Goor, H. Roelofsen, J. Baller, R. Havinga, H. J. Verkade, A. van Tol, P. L. M. Jansen, and F. Kuipers. Hyperlipidemia and atherosclerosis associated with liver disease in ferrochelatase-deficient mice. J. Lipid Res. 2001. 42: 41;-50.

Animals↗
PubMed2000

[Bile formation and cholestasis].

Transport proteins in hepatocytes and bile duct epithelium mediate uptake and secretion of cholephilic compounds in the liver and are involved in bile formation. Many of these proteins have recently been cloned and characterized and appear to belong to large gene families. Apart from the liver these proteins are expressed in the blood-brain barrier, placenta, kidneys, lungs, intestine and seminiferous tubules. Prokaryotes and yeasts contain similar proteins. In cancer cells they are involved in multidrug resistance. Some genetic cholestatic liver diseases, including progressive familial intrahepatic cholestasis, Dubin-Johnson syndrome, benign recurrent intrahepatic cholestasis and intrahepatic cholestasis of pregnancy result from mutations in transport protein genes. These proteins also play a role in drug-induced liver disease and in primary biliary cirrhosis. Cyclosporine and oestradiol (glucuronide) for instance inhibit bile salt export protein (BSEP).

Bile↗
PubMed2000

Multidrug resistance protein MRP1 protects against the toxicity of the major lipid peroxidation product 4-hydroxynonenal.

4-Hydroxynonenal (4HNE) is the most prevalent toxic lipid peroxidation product formed during oxidative stress. It exerts its cytotoxicity mainly by the modification of intracellular proteins. The detection of 4HNE-modified proteins in several degenerative disorders suggests a role for 4HNE in the onset of these diseases. Efficient protection mechanisms are required to prevent the intracellular accumulation of 4HNE. The toxicity of 4HNE was tested with the small cell lung cancer cell lines GLC(4) and the multidrug-resistance-protein (MRP1)-overexpressing counterpart GLC(4)/Adr. In the presence of the MRP1 inhibitor MK571 or the GSH-depleting agent buthionine sulphoximine, both cell lines became more sensitive and showed decreased survival. Transport experiments were performed with the (3)H-labelled glutathione S-conjugate of 4HNE ([(3)H]GS-4HNE) with membrane vesicles from GLC(4)-derived cell lines with different expression levels of MRP1. [(3)H]GS-4HNE was taken up in an ATP-dependent manner and the transport rate was dependent on the amount of MRP1. The MRP1 inhibitor MK571 decreased [(3)H]GS-4HNE uptake. MRP1-specific [(3)H]GS-4HNE transport was demonstrated with membrane vesicles from High Five insect cells overexpressing recombinant MRP1. Kinetic experiments showed an apparent K(m) of 1.6+/-0.21 microM (mean+/-S.D.) for MRP1-mediated [(3)H]GS-4HNE transport. In conclusion, MRP1 has a role in the protection against 4HNE toxicity and GS-4HNE is a novel MRP1 substrate. MRP1, together with GSH, is hypothesized to have a role in the defence against oxidative stress.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Association of human liver bilirubin UDP-glucuronyltransferase activity with a polymorphism in the promoter region of the UGT1A1 gene.

BACKGROUND/AIMS: Gilbert's syndrome is a benign form of a deficiency in bilirubin glucuronidation. It is associated with a homozygous polymorphism, A(TA)7TAA instead of A(TA)6TAA, in the TATA-box of the promoter region of the bilirubin UDP-glucuronyltransferase gene. In this study the correlation between this promoter region polymorphism and in vitro human liver bilirubin UDP-glucuronyltransferase enzyme activity was investigated. METHODS: Liver samples from organ transplant donors n=39) and two known Gilbert's syndrome patients were used for measuring bilirubin UDP-glucuronyltransferase enzyme activity and for isolation of DNA followed by detection of the promoter region polymorphism by polymerase chain reaction. Genotypes were assigned as follows; 6/6: homozygous for the A(TA)6TAA-allele, 7/7: homozygous for the A(TA)7TAA-allele, and 6/7: heterozygous with one of each alleles. RESULTS: Seventeen out of 39 subjects (44%) had the homozygous 6/6 genotype, 18 subjects (46%) had the heterozygous 6/7 genotype, whereas four individuals (10%) and the two individuals with Gilbert's syndrome had the 7/7 genotype correlated with Gilbert's syndrome. This resulted in an allele frequency of 0.33 for the A(TA)7TAA-allele. The median bilirubin UDP-glucuronyltransferase enzyme activity of the 17 subjects with the 6/6 genotype (1565 nmol/g liver/h) was significantly higher than the activity of the 18 subjects with the 6/7 genotype (985 nmol/g liver/h; p<0.05) and the six individuals with the 7/7 genotype (749 nmol/g liver/h; p<0.005). No significant differences in enzyme activity were found between the 6/7 and the 7/7 genotype groups. CONCLUSIONS: The results indicate a close association between the promoter region genotype and the expression of hepatic bilirubin UDP-glucuronyltransferase enzyme activity. Subjects who have a 7/7 genotype have the lowest enzyme activity, whereas subjects with the heterozygous 6/7 genotype have an intermediate enzyme activity.

Alleles↗
PubMed2000

The pathophysiology of cholestasis with special reference to primary biliary cirrhosis.

Cholestasis in primary biliary cirrhosis results from impairment of bile flow either by reduced transport at the level of the canaliculi or by disturbed bile flow through damaged intrahepatic bile ductules. Whatever its cause, the expression of hepatic transport proteins will be affected. In cholestatic rats: the expression of the multispecific organic anion transporter mrp2 is decreased; the bile salt export pump bsep and the phospholipid transporter mdr2 are less affected; the carrier protein for hepatic uptake of bile salts ntcp is sharply down-regulated; Mrp3, a basolateral ATP-dependent transporter for glucuronides and bile salts, is upregulated. Thus, bile salts that cannot exit the hepatocyte because of the cholestasis are effectively removed across the basolateral membrane. These may be adaptive responses in defence against overloading of hepatocytes with cytotoxic bile salts. These responses show that the expression of hepatic transporter proteins is highly regulated. This occurs by transcriptional and post-transcriptional mechanisms. Primary biliary cirrhosis starts as a disease of the small intrahepatic bile ducts and therefore the experimental evidence for 'cross-talk' between hepatocytes and cholangiocytes is of great interest for this disease and needs to be further investigated. New insights in bile physiology may enable the development of new therapies for cholestatic liver diseases as primary biliary cirrhosis.

Animals↗
PubMed2000

Genetic defects in hepatocanalicular transport.

Bile is made as the result of active transport of its constituents into the biliary space. Most of this transport occurs across the canalicular membrane, with a further contribution from cholangiocytes. Water moves passively into bile. The major substrates that are transported out of hepatocytes are bile acids, phospholipids, cholesterol, and bilirubin. With the exception of cholesterol, each of these major substrates is now recognized to have its own transport mechanism. In the case of bile acids and phospholipids, the transporters appear to be specific, though the bilirubin transporter is multispecific. Isolated autosomal recessive defects in all three of these transporters have now been identified and have helped to confirm the physiologic role of these proteins. In addition, a secondary defect in bile acid transport has been identified that appears to be due to an abnormality in plasma membrane aminophospholipid distribution.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Genetic cholestasis: lessons from the molecular physiology of bile formation.

Progressive familial intrahepatic cholestasis (PFIC) is a group of severe genetic cholestatic liver diseases of early life. PFIC types 1 and 2 are characterized by cholestasis and a low to normal serum gamma-glutamyltransferase (GGT) activity, whereas in PFIC type 3, the serum GGT activity is elevated. PFIC types 1 and 2 occur due to mutations in loci at chromosome 18 and chromosome 2, respectively. The pathophysiology of PFIC type 1 is not well understood. PFIC types 2 and 3 are caused by transport defects in the liver affecting the hepatobiliary secretion of bile acids and phospholipids, respectively. Benign recurrent intrahepatic cholestasis (BRIC) is linked to a mutation in the same familial intrahepatic cholestasis 1 locus at chromosome 18. Defects of bile acid synthesis may be difficult to differentiate from these transport defects. Intrahepatic cholestasis of pregnancy (ICP) appears to be related to these cholestatic diseases. For example, heterozygosity in families with PFIC type 3 is associated with ICP, but ICP has also been reported in families with BRIC. In Dubin-Johnson syndrome there is no cholestasis; only the hepatobiliary transport of conjugated bilirubin is affected. This, therefore, is a mild disease, and patients have a normal lifespan.

Bile↗
PubMed2000

Altered hepatobiliary disposition of acetaminophen glucuronide in isolated perfused livers from multidrug resistance-associated protein 2-deficient TR(-) rats.

Previous studies have demonstrated that phenobarbital treatment impairs the biliary excretion of acetaminophen glucuronide (AG), although the transport system(s) responsible for AG excretion into bile has not been identified. Initial studies in rat canalicular liver plasma membrane vesicles indicated that AG uptake was stimulated modestly by ATP, but not by membrane potential, HCO(3)(-), or pH gradients. To examine the role of the ATP-dependent canalicular transporter multidrug resistance-associated protein 2 (Mrp2)/canalicular multispecific organic anion transporter (cMOAT) in the biliary excretion of AG, the hepatobiliary disposition of acetaminophen, AG, and acetaminophen sulfate (AS) was examined in isolated perfused livers from control and TR(-) (Mrp2-deficient) Wistar rats. Mean bile flow in TR(-) livers was approximately 0.3 microl/min/g of liver ( approximately 4-fold lower than control). AG biliary excretion was decreased (>300-fold) to negligible levels in TR(-) rat livers, indicating that AG is an Mrp2 substrate. Similarly, AS biliary excretion in TR(-) livers was decreased ( approximately 5-fold); however, concentrations were still measurable, suggesting that multiple mechanisms, including Mrp2-mediated active transport, may be involved in AS biliary excretion. AG and AS perfusate concentrations were significantly higher in livers from TR(-) compared with control rats. Pharmacokinetic modeling of the data revealed that the rate constant for basolateral egress of AG increased significantly from 0.028 to 0.206 min(-1), consistent with up-regulation of a basolateral organic anion transporter in Mrp2-deficient rat livers. In conclusion, these data indicate that AG biliary excretion is mediated by Mrp2, and clearly demonstrate that substrate disposition may be influenced by alterations in complementary transport systems in transport-deficient animals.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2000

Foreword: from classic bile physiology to cloned transporters.

Uptake of drugs and metabolites from the circulation into the liver is facilitated by transporter proteins in the basolateral membrane of the hepatocyte. Among these proteins are the sodium taurocholate cotransporting protein, various multispecific transporters for organic anions and cations, transporters for glucose, amino acids, and prostaglandins. The canalicular membrane contains a number of ATP-dependent transporters belonging to the families of P-glycoproteins and multidrug resistance-associated proteins. Transport across the canalicular membrane represents the rate-determining step in the secretion of compounds from blood to bile. Mutations of genes encoding these canalicular transporters are associated with liver diseases such as progressive familial intrahepatic cholestasis and Dubin-Johnson syndrome. Wilson's disease appears to be due to a defect of a copper-transporting P-type ATPase. Also, bile ductuli contribute to bile formation. Mutations in the CFTR gene, encoding a chloride channel in bile duct epithelial cells, leads to the hepatic component of cystic fibrosis.

Bile↗
PubMed1999

Expression of inducible nitric oxide synthase in endotoxemic rat hepatocytes is dependent on the cellular glutathione status.

The inducible nitric oxide synthase (iNOS) promoter contains nuclear factor kappaB (NF-kappaB) binding sites. NF-kappaB activation is determined, in part, by the intracellular redox status. The aim of this study was to determine the importance of the cellular glutathione status in relation to NF-kappaB activation and iNOS expression in hepatocytes in vivo and in vitro. For in vivo experiments, rats were injected with endotoxin and sacrificed 6 hours later. Glutathione was depleted by diethylmaleate. For in vitro experiments, cultured hepatocytes from untreated rats were exposed to a cytokine mixture. Glutathione levels were depleted by diethylmaleate and restored by N-acetylcysteine. iNOS expression was assessed by Western blot, reverse transcription polymerase chain reaction, nitric oxide (NO) metabolites, and immunohistochemistry. NF-kappaB binding was assessed by electrophoretic mobility shift assay. Endotoxin-induced iNOS expression in rat liver was prominent in hepatocytes, Kupffer cells, and inflammatory cells, in particular neutrophils. Glutathione depletion prevented iNOS induction in hepatocytes, but not in inflammatory cells. iNOS protein levels were in accordance with iNOS messenger RNA and NO metabolites in plasma. Glutathione depletion did not affect neutrophil infiltration. Cytokines strongly induced iNOS in cultured hepatocytes. Induction was prevented by glutathione depletion and could be restored by addition of N-acetylcysteine. NF-kappaB binding correlated with iNOS induction. In conclusion, in this study we show that iNOS induction in hepatocytes in vivo and in vitro is dependent on the intracellular glutathione status and correlates with NF-kappaB binding. Glutathione-depletion has no effect on the expression of iNOS in inflammatory cells, nor on neutrophil infiltration.

Acetylcysteine↗
PubMed1999

Regulation of hepatic transport systems involved in bile secretion during liver regeneration in rats.

We investigated the expression of hepatic transport systems involved in bile secretion during liver regeneration after partial hepatectomy (PH) in rats. Initial studies showed maximal BrdU incorporation 24 hours after PH. Therefore, transporter expression and bile secretion were analyzed in detail at this time. The mRNA levels of the multidrug resistance genes mdr1a and mrp1 slightly increased, whereas mdr1b mRNA levels showed an extensive increase after PH. The mRNA levels of the conjugate transporter, mrp2, decreased slightly, whereas mrp2 protein levels did not change. Bilirubin secretion did not change, but the biliary glutathione secretion markedly decreased and the hepatic GSH content increased. The messenger RNA levels of the bile salt uptake transporters ntcp, oatp1, and oatp2 and the bile salt exporter, bsep/spgp, all decreased with ntcp showing the most prominent decrease. Protein levels of ntcp dramatically decreased whereas oatp2 only slightly decreased. Oatp1 protein expression slightly increased and bsep/spgp protein levels did not change. Decreased levels of bile salt uptake systems were associated with a 10-fold increase in the plasma bile salt concentration, yet, bile flow and bile salt secretion were increased when expressed per gram liver and unaffected when expressed on the basis of body weight. In conclusion, during the initial phase of rat liver regeneration ntcp is down-regulated whereas other transporter proteins involved in bile secretion are only slightly affected. Despite increased serum bile salt levels the remnant liver is not cholestatic: bile flow is maintained by uptake of bile salts probably via oatp isoforms and their secretion via bsep/spgp.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Diagnosis and management of Crigler-Najjar syndrome.

Crigler-Najjar syndrome (CNS) results from a mutation in one of the five exons of the gene coding for the enzyme bilirubin-UDP-glucuronosyltransferase by exon 1*1 and exons 2-5 of the UDP-glucuronosyltransferase 1 locus, the bilirubin glucuronidating isoform of UDP-glucuronosyltransferase. CNS type 2 is caused by a single base pair mutation leading to a decreased but not totally absent enzyme activity. In these patients the enzyme remains responsive to phenobarbital induction therapy and their bile contains low amounts of bilirubin mono- and diglucuronides. In CNS type 1 the enzyme activity is completely absent. CNS type 1 patients do not respond to phenobarbital and their bile does not contain more than traces of bilirubin conjugates. In 1997 we reported a World Registry on the treatment of patients with CNS type 1. Data were collected on 57 patients, of whom 21 (37%) had been transplanted at the time of data collection. Some 15 patients (26%) had brain damage, in 7 of whom the brain damage was mild and they received a liver transplant. Patients with brain damage at transplantation were significantly older than those without brain damage (14.3 vs 5.9 years). Before transplantation the serum bilirubin level of CNS type 1 patients should be kept below 350 micromol/l with daily phototherapy. Oral calcium supplementation makes phototherapy more efficient. Gene therapy has been performed successfully in the Gunn rat, an animal model for this disease. Liver cell transplantation has recently been done in a child with CNS type 1.

Animals↗