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Inge E T Van Den Berg - One of the best experts on this subject based on the ideXlab platform.
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extensive changes in liver gene expression induced by hereditary Tyrosinemia type i are not normalized by treatment with 2 2 nitro 4 trifluoromethylbenzoyl 1 3 cyclohexanedione ntbc
Journal of Hepatology, 2003Co-Authors: Marjanka C Luijerink, Ruud Berger, Saskia M M Jacobs, Ellen A C M Van Beurden, Leander P Koornneef, Leo W J Klomp, Inge E T Van Den BergAbstract:Abstract Background : Hereditary Tyrosinemia type I, caused by deficiency of fumarylacetoacetate hydrolase (FAH), is characterized by liver and kidney damage. Administration of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) corrects the Tyrosinemia phenotype, but does not prevent development of hepatocellular carcinoma. Aim : To gain insight into the pathophysiological changes associated with liver damage induced by Tyrosinemia and the preventive action of NTBC on these changes. Methods : Differential gene expression patterns in livers of Tyrosinemia-affected and healthy mice, and of Tyrosinemia-affected and NTBC-treated Fah −/− mice were investigated by suppression subtractive hybridization. Results : Transcripts encoding proteins playing a role in protein turnover, growth and proliferation, RNA processing, and signal transduction were primarily induced in Tyrosinemia-affected livers. Transcripts mainly contributing to the profile of suppressed genes encode proteins that are secreted by the liver, or are necessary for intermediate metabolism. NTBC treatment fails to normalize the Tyrosinemia-induced alterations in expression of transcripts encoding proteins involved in protein turnover, signal transduction, and cell growth and proliferation. Conclusions : The failure of NTBC to normalize liver gene expression of Fah −/− mice may play a role in rendering the Tyrosinemia-affected liver susceptible to development of hepatocellular carcinoma under NTBC treatment.
Edward A Lock - One of the best experts on this subject based on the ideXlab platform.
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Tyrosinemia produced by 2 2 nitro 4 trifluoromethylbenzoyl cyclohexane 1 3 dione ntbc in experimental animals and its relationship to corneal injury
Toxicology and Applied Pharmacology, 2006Co-Authors: Edward A Lock, M K Ellis, Peter Gaskin, William M Provan, L L SmithAbstract:2-(2-Nitro-4-trifluoromethylbenzoyl)-cyclohexane-1,3-dione (NTBC) is a potent inhibitor of rat liver 4-hydroxyphenylpyruvate dioxygenase (HPPD) leading to Tyrosinemia and corneal opacity. We examined the effect of NTBC on the extent of Tyrosinemia and production of corneal lesions in the beagle dog, rabbit and rhesus monkey, as part of safety evaluation on this drug. A single oral dose of 10 mg NTBC/kg to beagle dogs or rabbits increased the concentration of tyrosine in plasma and aqueous humour of the eye, the Tyrosinemia being both time- and dose-dependent. Hepatic HPPD was markedly inhibited with little effect on the activity of tyrosine aminotransferase (TAT) and homogentisic acid oxidase at the time of peak plasma tyrosine. Daily oral administration of NTBC to beagle dogs at 0.1, 0.5, 1.5 and 5 mg/kg/day produced corneal opacities with an incidence of 34% following 11 weeks of dosing, which reversed upon withdrawal of the drug. Tyrosine in plasma and aqueous humour was increased at all dose levels, 18 weeks after dosing. In contrast, daily oral administration of NTBC to rabbits for 6 weeks and rhesus monkeys for 12 weeks at 10 mg/kg/day produced no evidence of corneal opacities although tyrosine values were markedly increased. Our studies have shown that NTBC is a potent inhibitor of rabbit, beagle dog and by inference rhesus monkey liver HPPD producing a marked Tyrosinemia in all species studied, while only beagle dogs show corneal lesions. The production of corneal lesions in experimental animals exposed to NTBC does not appear to be simply related to the concentration of tyrosine in ocular fluid, other as yet unidentified factors appear to be necessary to trigger tissue injury.
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from toxicological problem to therapeutic use the discovery of the mode of action of 2 2 nitro 4 trifluoromethylbenzoyl 1 3 cyclohexanedione ntbc its toxicology and development as a drug
Journal of Inherited Metabolic Disease, 1998Co-Authors: Edward A Lock, M K Ellis, P Gaskin, M Robinson, T R Auton, W M Provan, Lewis L Smith, M P Prisbylla, L C MutterAbstract:NTBC is a triketone with herbicidal activity that has been shown to have a novel mode of action by inhibiting the enzyme 4-hydroxyphenylpyruvate dioxygenase in plants. Early studies on the toxicity of this compound found that rats treated with NTBC developed corneal lesions. Investigations aimed at understanding the mechanistic basis for the ocular toxicity discovered that the rats developed tyrosinaemia and excreted large amounts of 4-hydroxyphenylpyruvate and 4-hydroxyphenyllactate, owing to inhibition of the hepatic enzyme 4-hydroxyphenylpyruvate dioxygenase. The corneal lesions resemble those seen when rats are fed a diet supplemented with tyrosine, leading us to conclude that the ocular toxicity seen with NTBC is a consequence of a marked and sustained tyrosinaemia. Studies in collaboration with Professor Sven Lindstedt showed that NTBC was a potent inhibitor of purified human liver 4-hydroxyphenylpyruvate dioxygenase. This interaction lead to the concept of using NTBC to treat patients with tyrosinaemia type 1, to block or reduce the formation of toxic metabolites such as succinylacetoacetate in the liver. Zeneca Agrochemicals and Zeneca Pharmaceuticals made NTBC available for clinical use and, with the approval of the Swedish Medical Products Agency, a seriously ill child with an acute form of tyrosinaemia type 1 was successfully treated in February 1991. Subsequently, other children with this inborn error of metabolism in Sweden and other countries have been treated with NTBC. The drug is now available to those in need via Swedish Orphan AB.
Ruud Berger - One of the best experts on this subject based on the ideXlab platform.
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extensive changes in liver gene expression induced by hereditary Tyrosinemia type i are not normalized by treatment with 2 2 nitro 4 trifluoromethylbenzoyl 1 3 cyclohexanedione ntbc
Journal of Hepatology, 2003Co-Authors: Marjanka C Luijerink, Ruud Berger, Saskia M M Jacobs, Ellen A C M Van Beurden, Leander P Koornneef, Leo W J Klomp, Inge E T Van Den BergAbstract:Abstract Background : Hereditary Tyrosinemia type I, caused by deficiency of fumarylacetoacetate hydrolase (FAH), is characterized by liver and kidney damage. Administration of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) corrects the Tyrosinemia phenotype, but does not prevent development of hepatocellular carcinoma. Aim : To gain insight into the pathophysiological changes associated with liver damage induced by Tyrosinemia and the preventive action of NTBC on these changes. Methods : Differential gene expression patterns in livers of Tyrosinemia-affected and healthy mice, and of Tyrosinemia-affected and NTBC-treated Fah −/− mice were investigated by suppression subtractive hybridization. Results : Transcripts encoding proteins playing a role in protein turnover, growth and proliferation, RNA processing, and signal transduction were primarily induced in Tyrosinemia-affected livers. Transcripts mainly contributing to the profile of suppressed genes encode proteins that are secreted by the liver, or are necessary for intermediate metabolism. NTBC treatment fails to normalize the Tyrosinemia-induced alterations in expression of transcripts encoding proteins involved in protein turnover, signal transduction, and cell growth and proliferation. Conclusions : The failure of NTBC to normalize liver gene expression of Fah −/− mice may play a role in rendering the Tyrosinemia-affected liver susceptible to development of hepatocellular carcinoma under NTBC treatment.
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hereditary Tyrosinemia type i a new clinical classification with difference in prognosis on dietary treatment
Hepatology, 1994Co-Authors: J Francjan M D Van Spronsen, Ruud Berger, Yolande Thomasse, Peter G A Smit, James V Leonard, Peter E Clayton, Vaclav Fidler, Hugo S A HeymansAbstract:Hereditary Tyrosinemia type I (McKusick 27670) is a heterogeneous disease with poor prognosis, yet there are few reports of the long-term prognosis. It is therefore difficult to decide on the treatment for individual patients. We have conducted an international survey of patients with Tyrosinemia type I and examined the probability of survival on dietary treatment and the causes of death in 108 patients with Tyrosinemia type I. The survival after the onset of symptoms varied with the age at onset; the earlier the symptoms developed the poorer the outlook. Liver failure and recurrent bleeding (67%), hepatocellular carcinoma (17%) and the porphyria-like syndrome with respiratory failure (10%) were the most common causes of death. The 1- and 2-yr survival probability after the onset of symptoms in patients in whom symptoms developed before 2 mo, between 2 and 6 mo and after 6 mo were 38%/29%, 74%/74% and 96%/96%, respectively. On the basis of these survival rates, a new classification--which is important with respect to choices in treatment--is proposed: very early (onset of symptoms 6 mo).
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Tyrosinemia type 1 complex splicing defects and a missense mutation in the fumarylacetoacetase gene
Human Genetics, 1994Co-Authors: Tom Kristensen, Ruud Berger, Kari Hoie, E A KvittingenAbstract:Two mutations are reported in six Tyrosinemia type 1 patients from northern Europe. In four patients, a G to A transition at nucleotide position 1009 (G1009→A) of the fumarylacetoacetase (FAH) coding sequence caused aberrant splicing by introducing an acceptor splice site within exon 12, thereby deleting the first 50 nucleotides of this exon. The following exon-intron boundary was frequently missed, and a cryptic donor splice site within intron 12 caused a partial intron 12 retention of 105 bp. This point mutation alternatively gave a glycine 337 to serine substitution in instances of correct splicing. The mutation is rapidly detected by PvuII digestion of polymerase chain reaction (PCR)-amplified genomic DNA. Another mutation, g+5→a in the intron 12 donor splice site consensus sequence (IVS12 g+5→a), was found in five of the patients. This caused alternative splicing with retention of the first 105 nucleotides of intron 12, exon 12 skipping, and a combined deletion of exons 12 and 13. Rapid detection of this mutation is achieved by restriction digestion of PCR-amplified genomic DNA; a mismatch primer combined with the point mutation creates a Tru9I restriction site. One patient who was homozygous for the G1009→A mutation had a chronic form of Tyrosinemia. Three patients were combined heterozygotes for G1009→A and TVS12 g+5→a. Their clinical phenotypes varied from acute to chronic, indicating the impact of background genes and/or external factors on the presentation of typrosinemia type 1.
L C Mutter - One of the best experts on this subject based on the ideXlab platform.
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from toxicological problem to therapeutic use the discovery of the mode of action of 2 2 nitro 4 trifluoromethylbenzoyl 1 3 cyclohexanedione ntbc its toxicology and development as a drug
Journal of Inherited Metabolic Disease, 1998Co-Authors: Edward A Lock, M K Ellis, P Gaskin, M Robinson, T R Auton, W M Provan, Lewis L Smith, M P Prisbylla, L C MutterAbstract:NTBC is a triketone with herbicidal activity that has been shown to have a novel mode of action by inhibiting the enzyme 4-hydroxyphenylpyruvate dioxygenase in plants. Early studies on the toxicity of this compound found that rats treated with NTBC developed corneal lesions. Investigations aimed at understanding the mechanistic basis for the ocular toxicity discovered that the rats developed tyrosinaemia and excreted large amounts of 4-hydroxyphenylpyruvate and 4-hydroxyphenyllactate, owing to inhibition of the hepatic enzyme 4-hydroxyphenylpyruvate dioxygenase. The corneal lesions resemble those seen when rats are fed a diet supplemented with tyrosine, leading us to conclude that the ocular toxicity seen with NTBC is a consequence of a marked and sustained tyrosinaemia. Studies in collaboration with Professor Sven Lindstedt showed that NTBC was a potent inhibitor of purified human liver 4-hydroxyphenylpyruvate dioxygenase. This interaction lead to the concept of using NTBC to treat patients with tyrosinaemia type 1, to block or reduce the formation of toxic metabolites such as succinylacetoacetate in the liver. Zeneca Agrochemicals and Zeneca Pharmaceuticals made NTBC available for clinical use and, with the approval of the Swedish Medical Products Agency, a seriously ill child with an acute form of tyrosinaemia type 1 was successfully treated in February 1991. Subsequently, other children with this inborn error of metabolism in Sweden and other countries have been treated with NTBC. The drug is now available to those in need via Swedish Orphan AB.
M K Ellis - One of the best experts on this subject based on the ideXlab platform.
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Tyrosinemia produced by 2 2 nitro 4 trifluoromethylbenzoyl cyclohexane 1 3 dione ntbc in experimental animals and its relationship to corneal injury
Toxicology and Applied Pharmacology, 2006Co-Authors: Edward A Lock, M K Ellis, Peter Gaskin, William M Provan, L L SmithAbstract:2-(2-Nitro-4-trifluoromethylbenzoyl)-cyclohexane-1,3-dione (NTBC) is a potent inhibitor of rat liver 4-hydroxyphenylpyruvate dioxygenase (HPPD) leading to Tyrosinemia and corneal opacity. We examined the effect of NTBC on the extent of Tyrosinemia and production of corneal lesions in the beagle dog, rabbit and rhesus monkey, as part of safety evaluation on this drug. A single oral dose of 10 mg NTBC/kg to beagle dogs or rabbits increased the concentration of tyrosine in plasma and aqueous humour of the eye, the Tyrosinemia being both time- and dose-dependent. Hepatic HPPD was markedly inhibited with little effect on the activity of tyrosine aminotransferase (TAT) and homogentisic acid oxidase at the time of peak plasma tyrosine. Daily oral administration of NTBC to beagle dogs at 0.1, 0.5, 1.5 and 5 mg/kg/day produced corneal opacities with an incidence of 34% following 11 weeks of dosing, which reversed upon withdrawal of the drug. Tyrosine in plasma and aqueous humour was increased at all dose levels, 18 weeks after dosing. In contrast, daily oral administration of NTBC to rabbits for 6 weeks and rhesus monkeys for 12 weeks at 10 mg/kg/day produced no evidence of corneal opacities although tyrosine values were markedly increased. Our studies have shown that NTBC is a potent inhibitor of rabbit, beagle dog and by inference rhesus monkey liver HPPD producing a marked Tyrosinemia in all species studied, while only beagle dogs show corneal lesions. The production of corneal lesions in experimental animals exposed to NTBC does not appear to be simply related to the concentration of tyrosine in ocular fluid, other as yet unidentified factors appear to be necessary to trigger tissue injury.
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from toxicological problem to therapeutic use the discovery of the mode of action of 2 2 nitro 4 trifluoromethylbenzoyl 1 3 cyclohexanedione ntbc its toxicology and development as a drug
Journal of Inherited Metabolic Disease, 1998Co-Authors: Edward A Lock, M K Ellis, P Gaskin, M Robinson, T R Auton, W M Provan, Lewis L Smith, M P Prisbylla, L C MutterAbstract:NTBC is a triketone with herbicidal activity that has been shown to have a novel mode of action by inhibiting the enzyme 4-hydroxyphenylpyruvate dioxygenase in plants. Early studies on the toxicity of this compound found that rats treated with NTBC developed corneal lesions. Investigations aimed at understanding the mechanistic basis for the ocular toxicity discovered that the rats developed tyrosinaemia and excreted large amounts of 4-hydroxyphenylpyruvate and 4-hydroxyphenyllactate, owing to inhibition of the hepatic enzyme 4-hydroxyphenylpyruvate dioxygenase. The corneal lesions resemble those seen when rats are fed a diet supplemented with tyrosine, leading us to conclude that the ocular toxicity seen with NTBC is a consequence of a marked and sustained tyrosinaemia. Studies in collaboration with Professor Sven Lindstedt showed that NTBC was a potent inhibitor of purified human liver 4-hydroxyphenylpyruvate dioxygenase. This interaction lead to the concept of using NTBC to treat patients with tyrosinaemia type 1, to block or reduce the formation of toxic metabolites such as succinylacetoacetate in the liver. Zeneca Agrochemicals and Zeneca Pharmaceuticals made NTBC available for clinical use and, with the approval of the Swedish Medical Products Agency, a seriously ill child with an acute form of tyrosinaemia type 1 was successfully treated in February 1991. Subsequently, other children with this inborn error of metabolism in Sweden and other countries have been treated with NTBC. The drug is now available to those in need via Swedish Orphan AB.
