Disease relevance of Agxt

• Further analysis and consideration of these interspecific differences will be essential for the development of meaningful animal models to probe the mechanism by which AGT may predispose to human essential hypertension [1].
• On the other hand, the restricted specificity of Escherichia coli AGT to repair of O6-methylguanine makes the assay based on it specific for this type of lesion (detection limit, 0.5 fmol) [2].
• Prior to underperfusion, hearts (n = 6 per group) were subjected to two cycles of either preconditioning ischemia (PC), infusion of the adenosine A1 agonist 2-chloro-N6-cyclopentyladenosine (CCPA; 0.25 mumol/l), or PC in the presence of the adenosine antagonist 8-(p-sulfophenyl)theophylline (SPT; 50 mumol/l) [3].
• The AGT activity in the thymus of Long-Evans strain, which had a low incidence of PNU-induced thymic lymphomas, was higher than that of F344 strain [4].
• CONCLUSIONS: Vitamin B6 deficiency not only decreased alanine-glyoxylate aminotransferase activity, but also down-regulated alanine-glyoxylate aminotransferase gene expression by hepatocytes and led to hyperoxaluria and hyperglycolic aciduria secondary to impaired metabolism of oxalate precursors [5].

High impact information on Agxt

• The ability of NNKOAc-treated DNA to inhibit AGT was destroyed when the DNA was subjected to neutral thermal hydrolysis [6].
• When hepatocytes had been precultured for 16-18 h under serum- and hormone-free conditions, the addition of glucagon caused (after a lag period of about 2 h) a remarkable increase in the cellular level of SPT/AGT mRNA by 4 h in a time- and dose-dependent manner [7].
• The effects of glucagon on serine: pyruvate/alanine: glyoxylate aminotransferase (SPT/AGT) gene expression were studied in primary cultured rat hepatocytes [7].
• The glucagon-induced expression of the SPT/AGT gene was also turned off by dexamethasone [7].
• When 2 x 5 mg/kg SPT (a dose selective for A(1)-receptors, as it did not affect the protection by the A(3) selective agonist IB-MECA, 51+/-3%) and MRS 1191 were combined the protection by IP was abolished (IS=67+/-2%) [8].

Chemical compound and disease context of Agxt

• N(G)-nitro-L-arginine methyl ester (L-NAME, 30 microM), a nonselective nitric oxide synthase inhibitor, or SPT (50 microM) administered for 10 min prior to the low-flow ischemia cancelled the effects [9].
• After 30-min low-flow ischemia, vasodilation, still present at reperfusion, was completely abolished by resveratrol plus adenosine antagonist 8-(p-sulfophenyl)theophylline (SPT, 50 microM) administration [9].

Biological context of Agxt

• Determination of the nucleotide sequence up to -1.25 kb from the transcription initiation site revealed the presence of many putative cis elements, some of which may explain the transcriptional regulation of the SPT/AGT gene by glucagon and glucocorticoid [10].
• The SPT/AGT gene consists of 11 exons, and the exon-intron boundaries have typical splice donor and acceptor sequences [10].
• The direct proof that promoter variants of AGT can lead to elevated blood pressure will ultimately require the development of specific animal models [1].
• Before such work can be contemplated, however, a formal understanding of the mechanisms controlling transcriptional activation of AGT needs to be developed [1].
• Several genetic polymorphisms have been identified in the proximal promoter of angiotensinogen ( AGT) [1].

Anatomical context of Agxt

• Analysis of DNA-protein interactions in vitro and transactivation experiments in cultured cells reveal the critical role of an Sp1 binding site immediately upstream of the TATA box of AGT in both mouse and human [1].
• Most of alanine-glyoxylate aminotransferase activity was localized in the mitochondria, with some activity in the peroxisomes [11].
• This suggests the presence of O6-alkylguanine DNA alkyltransferase (AGT) in thymus [4].
• However, the AGT levels of the mammary gland and brain were in the range of 45-61% (expressed relative to protein content) and 39-54% (expressed relative to homogenate DNA content) of those of the saline-treated controls [12].
• A similar depletion and slow recovery of AGT in the liver, blood lymphocytes, bone marrow and lymph nodes was observed after treatment with a single dose of 100 mg/kg procarbazine [13].

Associations of Agxt with chemical compounds

• It is based on the use of the suicide repair enzyme O6-alkylguanine-DNA-alkyltransferase (AGT) to repair such adducts in DNA in competition with an oligonucleotide containing a single residue of O6-methylguanine, end labeled to high specific activity [2].
• It is concluded that procarbazine (but not MNU) causes a decrease in cellular AGT concentrations by a mechanism additional to suicide repair of O6-meG.(ABSTRACT TRUNCATED AT 400 WORDS)[13]
• The improved functional recovery was not significantly affected by an ecto-5'-nucleotidase inhibitor, alpha,beta-methylene adenosine diphosphate (AMP-CP; 100 microM), alone but was inhibited by AMP-CP plus SPT, suramin, or RB [14].
• Hepatic alanine-glyoxylate aminotransferase activity and its mRNA level were significantly lower in vitamin B6 deficient rats than in control rats [5].
• Therefore, we evaluated hepatic alanine-glyoxylate aminotransferase activity and oxalate metabolism in vitamin B6 deficient rats [5].

Other interactions of Agxt

• These properties and kinetic parameters of the enzyme are remarkably similar to those previously described for mitochondrial alanine-glyoxylate aminotransferase isoenzyme 1 from glucagon-injected rat liver [Noguchi, Okuno, Takada, Minatogawa, Okai & Kido (1978, Biochem. J. 169, 113-122] [15].

Analytical, diagnostic and therapeutic context of Agxt

• Gene titration experiments in transgenic animals have demonstrated that small increases in the basal expression of AGT can lead to elevated blood pressure [1].
• RESULTS: At the end of reperfusion, recovery of rate-force product was enhanced in the PC and CCPA groups (62 and 67% of preischemic value) compared to the ischemic control hearts (IC, 32%; P < 0.05), whereas protection was abolished in the SPT hearts (20%; P < 0.05 vs. PC) [3].
• In contrast to these observations, O6-meG accumulated smoothly during a 10 day administration of MNU (1 or 10 mg/kg/day) to reach a steady-state within 5-6 days, while liver AGT was partially depleted after the high dose and recovered fully within 72 h of cessation of treatment [13].
• SPT (100 mumol/l) and HOE 140 did not interfere with ischemic preconditioning (infarct size: 7.8 +/- 1.1%) [16].
• In the present study, the location of the rat SPT/AGT gene was determined to be in the q34-q36 region of chromosome 9 by fluorescence in situ hybridization [17].

References