Source:http://linkedlifedata.com/resource/pubmed/id/12899938
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
4
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| pubmed:dateCreated |
2003-8-5
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| pubmed:abstractText |
Whereas ch/ch wild-type mice and ch/14CoS heterozygotes are viable, 14CoS/14CoS mice homozygous for a 3800 kb deletion on chromosome 7 die during the first day postpartum. Death is caused by disruption of the fumarylacetoacetate hydrolase (Fah) gene; absence of FAH, final enzyme in the tyrosine catabolism pathway, leads to accumulation of reactive electrophilic intermediates. In this study, we kept 14CoS/14CoS mice alive for 60 d with oral 2-(2-nitro-4-trifluoromethyl-benzyol)-1,3-cyclohexanedione (NTBC), an inhibitor of p-hydroxyphenylpyruvate dioxygenase, second enzyme in the tyrosine catabolic pathway. The 70% of NTBC-treated 14CoS/14CoS mice that survived 60 d showed poor growth and developed corneal opacities, compared with ch/14CoS littermates; NTBC-rescued Fah(-/-) knockout mice did not show growth retardation or ocular toxicity. NTBC-rescued 14CoS/14CoS mice also exhibited a striking oxidative stress response in liver and kidney, as measured by lower GSH levels and mRNA induction of four genes: glutamate cysteine ligase catalytic (Gclc) and modifier (Gclm) subunits, NAD(P)H:quinone oxidoreductase (Nqo1), and heme oxygenase-1 (Hmox1). Withdrawal of NTBC for 24-48 h from rescued adult 14CoS/14CoS mice resulted in severe apoptosis of the liver, detected histologically and by cytochrome c release from the mitochondria, increased caspase 3-like activity, and further decreases in GSH content. In kidney, proximal tubular epithelial cells were abnormal. Human hereditary tyrosinemia type I (HT1), caused by mutations in the FAH gene, is an autosomal recessive disorder in which the patient usually dies of liver fibrosis and cirrhosis during early childhood; NTBC treatment is known to prolong HT1 children's lives-although liver fibrosis, cirrhosis, hepatocarcinoma, and corneal opacities sometimes occur. The mouse data in the present study are consistent with the possibility that endogenous oxidative stress-induced apoptosis may be the underlying cause of liver pathology seen in NTBC-treated HT1 patients.
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| pubmed:grant | |
| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/CASP3 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Casp3 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Caspase 3,
http://linkedlifedata.com/resource/pubmed/chemical/Caspases,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclohexanones,
http://linkedlifedata.com/resource/pubmed/chemical/Free Radicals,
http://linkedlifedata.com/resource/pubmed/chemical/Glutamate-Cysteine Ligase,
http://linkedlifedata.com/resource/pubmed/chemical/Glutathione,
http://linkedlifedata.com/resource/pubmed/chemical/Hydrolases,
http://linkedlifedata.com/resource/pubmed/chemical/Nitrobenzoates,
http://linkedlifedata.com/resource/pubmed/chemical/RNA,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger,
http://linkedlifedata.com/resource/pubmed/chemical/Tyrosine,
http://linkedlifedata.com/resource/pubmed/chemical/fumarylacetoacetase,
http://linkedlifedata.com/resource/pubmed/chemical/nitisinone
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| pubmed:status |
MEDLINE
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| pubmed:month |
Aug
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| pubmed:issn |
0891-5849
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| pubmed:author | |
| pubmed:issnType |
Print
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| pubmed:day |
15
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| pubmed:volume |
35
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
351-67
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| pubmed:dateRevised |
2007-11-14
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| pubmed:meshHeading |
pubmed-meshheading:12899938-Animals,
pubmed-meshheading:12899938-Apoptosis,
pubmed-meshheading:12899938-Caspase 3,
pubmed-meshheading:12899938-Caspases,
pubmed-meshheading:12899938-Cyclohexanones,
pubmed-meshheading:12899938-Free Radicals,
pubmed-meshheading:12899938-Glutamate-Cysteine Ligase,
pubmed-meshheading:12899938-Glutathione,
pubmed-meshheading:12899938-Hepatocytes,
pubmed-meshheading:12899938-Heterozygote,
pubmed-meshheading:12899938-Humans,
pubmed-meshheading:12899938-Hydrolases,
pubmed-meshheading:12899938-Kidney,
pubmed-meshheading:12899938-Liver,
pubmed-meshheading:12899938-Mice,
pubmed-meshheading:12899938-Mice, Knockout,
pubmed-meshheading:12899938-Mice, Transgenic,
pubmed-meshheading:12899938-Microscopy, Electron,
pubmed-meshheading:12899938-Models, Chemical,
pubmed-meshheading:12899938-Nitrobenzoates,
pubmed-meshheading:12899938-Oxidative Stress,
pubmed-meshheading:12899938-Protein Structure, Tertiary,
pubmed-meshheading:12899938-RNA,
pubmed-meshheading:12899938-RNA, Messenger,
pubmed-meshheading:12899938-Time Factors,
pubmed-meshheading:12899938-Tyrosine,
pubmed-meshheading:12899938-Tyrosinemias
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| pubmed:year |
2003
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| pubmed:articleTitle |
Pharmacological rescue of the 14CoS/14CoS mouse: hepatocyte apoptosis is likely caused by endogenous oxidative stress.
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| pubmed:affiliation |
Department of Environmental Health and Center for Environmental Genetics (CEG), University of Cincinnati Medical Center, Cincinnati, OH, USA.
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| pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.
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