Disease relevance of Triacetyloleandomycin

• Trial of iloprost versus aspirin treatment for critical limb ischaemia of thromboangiitis obliterans. The TAO Study [1].
• (2) Toxicity was prevented by pretreatment with a single dose of troleandomycin (a specific inhibitor of cytochromes P4503A) and enhanced by pretreatment with dexamethasone or clotrimazole (two inducers of cytochromes P4503A) [2].
• Consistently, modulation of the tunnel shape, caused by the binding of the semi-synthetic macrolide troleandomycin to the large ribosomal subunit from Deinococcus radiodurans, was revealed crystallographically [3].
• In vivo antitumor activity experiments revealed that TAO completely suppressed the ability of 90 microg/kg MMDX i.v., a dose close to the LD10, to delay growth of s.c. M5076 tumors in C57BL/6 mice and to prolong survival of DBA/2 mice with disseminated L1210 leukemia [4].
• Moreover, TAO administration markedly inhibited the therapeutic efficacy of 90 microg/kg MMDX i.v. in mice bearing experimental M5076 liver metastases; a complete loss of MMDX activity was observed in liver metastases-bearing animals receiving 40 microg/kg MMDX i.v. plus TAO [4].

Psychiatry related information on Triacetyloleandomycin

• Troleandomycin was found to prolong the psychomotor impairment and amnesia produced by triazolam [5].

High impact information on Triacetyloleandomycin

• Here we show that, in addition to the typical steric blockage of the ribosomal tunnel by macrolides, troleandomycin induces a conformational rearrangement in a wall constituent, protein L22, flipping the tip of its highly conserved beta-hairpin across the tunnel [3].
• In contrast, cell death was prevented by decreasing CYP3A activity (with troleandomycin), preventing glutathione depletion (with cysteine or cystine), blocking Ca(2+)-modulated events (with calmidazolium), preventing mitochondrial permeability transition (with cyclosporin A), or inhibiting caspase 3 (with acetyl-Asp-G u-Va-Asp-a dehyde) [6].
• Pretreatment of male rats with troleandomycin, an inhibitor of cytochrome P450 3A (CYP3A), slowed the depletion of glutathione and decreased toxicity, whereas dexamethasone, an inducer of CYP3A, had opposite effects [7].
• It was inhibited, both in human hepatocytes and in liver microsomes, by typical CYP3A substrates and/or inhibitors such as erythromycin, ketoconazole, nifedipine, midazolam, and troleandomycin [8].
• The TAO (for thousand-and-one amino acids) protein kinases activate p38 mitogen-activated protein (MAP) kinase cascades in vitro and in cells by phosphorylating the MAP/ERK kinases (MEKs) 3 and 6 [9].

Chemical compound and disease context of Triacetyloleandomycin

• Inhibition of glucocorticoid 6 beta-hydroxylation by troleandomycin did not modify adrenocorticotrophin-induced hypertension, suggesting that effects of corticosterone 6 beta-hydroxylation in adrenocorticotrophin-induced hypertension are negligible [10].
• The data obtained by treating H56 and S-H56-125 hepatoma cells with different P450 inducers (dexamethasone (DEX), benzanthracene, phenobarbital) or with a specific P450 inhibitor, troleandomycin, led us to conclude that CYP3A is involved in the hydroxylation of RU486 [11].
• A single dose of troleandomycin completely reversed the ability of PCN to protect rats from digitoxin toxicity, establishing the importance of cytochrome P-450p induction in the protective effect of PCN [12].
• When ergopeptide metabolism is inhibited by the presence of macrolide antibacterials, particularly troleandomycin and erythromycin, the resultant interaction can produce ergotism, sometimes leading to gangrene [13].
• The biotransformation of both compounds by pyridine- and phenobarbital-induced rat liver microsomes and the inhibition of LDH release by 4-methylpyrazole and troleandomycin indicate that P450 2E1, 2B and, possibly, also 3A are the isoforms involved in the bioactivation and toxicity of HCFC-123 and HCFC-141b in the rat [14].

Biological context of Triacetyloleandomycin

• In contrast, troleandomycin, a selective inhibitor of CYP3A3 and -3A4, and anti-CYP3A IgG substantially inhibited microsomal ifosphamide hydroxylation but had little or no effect on microsomal cyclophosphamide hydroxylation [15].
• The macrolide class of antibiotics, including erythromycin and troleandomycin, is associated with clinically significant adverse drug interactions [16].
• We prepared a cDNA library from TAO induced rabbit liver mRNA and characterized a cDNA (pLM3c-4.1) that hybridized to pDex 3.22, a cDNA complementary to cytochrome P-450p mRNA [17].
• This blood pressure increase was attenuated by troleandomycin (40 mg/kg) given either during or after development of hypertension [18].
• With the use of cells incubated with [3H]dexamethasone at 22 degrees C, we examined the competitive binding properties of TAO and OLEO (at varying concentrations) with and without MP as compared with several other steroids and MP alone [19].

Anatomical context of Triacetyloleandomycin

• Cytochrome P-450 isozyme LM3b from rabbit liver microsomes. Induction by triacetyloleandomycin purification and characterization [20].
• To investigate the mechanism of induction of P-450p, we treated rats for 4 days with these agents and found that dexamethasone and TAO induced the synthesis of P-450p at least 70- and 35-fold over control values, respectively, as estimated from measurements of P-450p mRNA translatable in a cell-free system [21].
• Prior incubation of microsomes with gestodene (100 microM) or troleandomycin (20 microM), known selective mechanism-based inhibitors of P-4503A enzymes (in the presence of NADPH), led to 75% and 40% reductions in catalytic activity, respectively [22].
• We tested the latter possibility by studying the interaction of TAO and oleandomycin phosphate (OLEO), the active metabolite of TAO in vivo, with glucocorticoid receptors in dispersed, intact cultured human skin fibroblasts [19].
• Mast cell stabilizers, anticholinergics, corticosteroids, and troleandomycin [23].

Associations of Triacetyloleandomycin with other chemical compounds

• The formation of metabolite M4 was substantially reduced both by antibody directed against CYP3A and by the addition of CYP3A substrates such as orphenadrine, erythromycin, troleandomycin, and testosterone [24].
• Northern blots of liver poly(A)RNA from untreated or TAO, erythromycin and rifampicin treated animals, revealed two mRNA species of approximately 1700 and 1850 nucleotides in length, that hybridized to LM3c cDNA and to pDEX 3.22 [17].
• Activity in recombinant CYP3A4 and pooled liver microsomes was dose-dependently inhibited by ketoconazole, troleandomycin, isoniazid, and alpha-naphthoflavone, known inhibitors of CYP3A4 [25].
• Methylprednisolone clearance before TAO was at least 4 times faster than normal and was probably related to enzyme induction by the anticonvulsant medication [26].
• Each volunteer received 1 mg intravenous midazolam, followed 1 hour later by 15 microg/kg intravenous alfentanil, after CYP3A4 induction (rifampin [INN, rifampicin]), CYP3A4 inhibition (troleandomycin), and control [27].

Gene context of Triacetyloleandomycin

• Evaluation of triacetyloleandomycin, alpha-naphthoflavone and diethyldithiocarbamate as selective chemical probes for inhibition of human cytochromes P450 [28].
• In the present study we take advantage of recent advances in cDNA-directed human P450 expression to evaluate directly the P450 form selectivity of TAO, ANF, and DDC, using a panel of 10 individual cDNA-expressed human P450s [28].
• Triacetyloleandomycin inhibited the reaction by approximately 90%, suggesting that CYP3A7 was primarily responsible for catalyzing the reaction [29].
• The addition of the CYP3A subfamily selective inhibitor triacetyloleandomycin (1 microM) produced no statistically significant inhibition in reactions catalyzed by CYP1A1 or 1B1 SUPERSOMES [29].
• Using furafyllin and troleandomycin to inhibit CYP1A2 and CYP3A4 in liver microsomes, it was found that the 2-hydroxylation had been inhibited about the same amount [30].

Analytical, diagnostic and therapeutic context of Triacetyloleandomycin

• Oral administration of triacetyloleandomycin (TAO), 1 mmol/kg/day for 7 days to mature male New Zealand White rabbit results in a significant increase in the content of liver microsomal cytochrome P-450 [20].
• High-performance liquid chromatography analysis revealed that RASMC were capable to metabolize CsA to its primary metabolites (AM1, AM9 and AM4N), and that their formation was inhibited by ketoconazole and troleandomycin [31].
• RESULTS: Treatment with MP and TAO resulted in a clear reduction in respiratory symptoms, asthmatic attacks, corticosteroid and hospitalization requirements, improvement in pulmonary function tests, and a remarkable decrease in peak expiratory flow rate circadian variability when compared with the period before TAO treatment (with corticosteroids) [32].
• The activities and levels of P450IIIA in hepatic microsomes from maternal rats and fetuses at 15-21 days of gestation were measured by triacetyloleandomycin (TAO) inhibited debenzylation of (benzyloxy)phenoxazone and by immunoassay with defined antiserum specific for P450IIIA [33].
• The aim of treatment in patients with TAO is to make patients abstain from smoking to prevent ulceration and to shorten the period of healing of trophic lesions without major amputation, as ulceration and gangrene in T AO are limited to the most distal part of the limbs, and seems to have healing potential [34].

References