Disease relevance of Fah

• Fumarylacetoacetate hydrolase (FAH) is an enzyme which is deficient in human hereditary tyrosinemia type 1 [1].
• The early target Mr 14,000 protein of the carcinogen in normal rats was identified as being liver fatty acid-binding protein and was associated in hepatocytes with normal mitosis and the cell proliferation brought about by either of the two liver carcinogens, FAA or 3'-methyl-4-dimethylaminoazobenzene [2].
• However, a cause and effect relationship between FAA liberation and the evolution of ischemic brain injury must be established before accurate predictions of efficacy can be made by this method [3].
• The link between kidney toxicants and inherited tyrosinaemia also raises the possibility that FAH may be a marker of kidney toxicity in humans [4].
• The 8 tumour free animals were rechallenged with MC7 sarcoma 40 weeks later, without further FAA treatment [5].

High impact information on Fah

• The number of altered liver cell foci in rats given 200 ppm N-2-fluorenylacetamide (FAA; CAS: 53-96-3) in the diet for 8 weeks and followed by the betel nut diet for 16 weeks was significantly greater than that in animals fed the FAA diet alone [6].
• Continued ingestion of any of the three hepatocarcinogens, FAA, 3'-methyl-4-dimethylaminoazobenzene, or ethionine, resulted in the progressive loss of the early radioactive complex and the concurrent gain in liver cytosol of the late carcinogen: protein complex (Mr approximately 150,000) formed by the tracer dose of FAA [2].
• This work examines whether 2-(2-nitro-4-trifluoromethylbenzoyl)-cyclohexane-1,3-dione (NTBC), a potent inhibitor of the enzyme 4-hydroxyphenylpyruvate dioxygenase (HPPD) located upstream of FAH, modulates D-serine-induced nephrotoxicity [7].
• FAH is involved in tyrosine catabolism; hence, this pathway may be involved in mediating the toxicity [7].
• We describe a new method for the asymmetric synthesis of [(18)F]fluorinated aromatic alpha-amino acids (FAA) under phase transfer conditions using achiral glycine derivative NiPBPGly and (S)-NOBIN as a novel substrate/catalyst pair [8].

Chemical compound and disease context of Fah

• Tyrosinemia type 1 (HT1) is an autosomal recessive disorder of the tyrosine metabolism in which the fumarylacetoacetate hydrolase enzyme is defective [9].
• Experiment 2: The incidence of altered hepatocellular foci in female ACI/N rats given N-2-fluorenylacetamide (FAA, 0.02% in diet) for 10 wk and reserpine (weekly subcutaneous injections, 1 microgram/g body weight) during or after (17 wk) FAA exposure was significantly lower than that of rats given FAA alone [10].
• The toxicity in rats and mice and the responses of 5 rat lung tumours, a rat rhabdomyosarcoma and a mouse colon tumour to flavone acetic acid, FAA, were studied [11].
• Experiment 3: The number of hepatocellular foci in male ACI/N rats given 0.02% FAA diet for 13 wk and E-5166 by gavage (40 mg/kg body weight, 3 times/wk) for 16 wk after the end of FAA exposure was significantly smaller than that in rats given FAA diet alone [10].

Biological context of Fah

• The LD50 values of FAA in WAG/Rij and BN rats were about 350 and 525 mg/kg respectively, independent of whether the animals were tumour bearing or not [11].

Anatomical context of Fah

• In previous studies, administration of a radioactive tracer dose of the liver carcinogen, N-2-fluorenylacetamide (2-acetylaminofluorene; FAA), to normal or carcinogen-fed rats led to the presence of one or two principal labeled carcinogen: protein complexes in liver cytosol [2].
• As a step towards the cloning of the gene for fumarylacetoacetate hydrolase (FAH), we have purified the FAH mRNA from rat liver by specific immunoadsorption of polysomes [12].

Associations of Fah with chemical compounds

• FAH was elevated in the plasma of animals treated with 4-AP and D-serine at early time points and returned to baseline levels after 3 weeks [4].
• One toxicity-associated plasma protein was identified as the cellular enzyme fumarylacetoacetate hydrolase (FAH), which is known to be required for tyrosine metabolism [4].
• Therefore, FAH may function in a fashion analogous to the aspartate aminotransferase (AST) and alanine aminotransferase (ALT) enzymes that are used to measure liver injury [4].
• The effects of the anti-rheumatic drugs indometacin, dexamethasone, cyclophosphamide and cyclosporin A (CsA) on IL-6 levels during FAA were determined [13].

Analytical, diagnostic and therapeutic context of Fah

• Northern blot analysis indicates that the kidney contains slightly more FAH mRNA that the liver [1].
• Western blotting shows, however, that the liver contains about twice as much FAH protein as the kidney [1].
• The levels of serum interleukin-6 (IL-6) were measured during the course of adjuvant arthritis (FAA) in male Lewis rats [13].

References