Disease relevance of Dpys

• Riddelliine requires metabolic activation to dehydroriddelliine and 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP) to exert its toxicity [1].
• These amounts can then be compared to acute doses producing pneumotoxicity in vivo (given in parentheses): DHP, 13 mumol/kg body weight released (350 mumol/kg); GSDHP, 8 mumol/kg (300 mumol/kg); and dehydromonocrotaline, 14 mumol/kg (15 mumol/kg) [2].
• Relative potency analysis revealed that alpha DHP, 3 alpha,5 beta-Pgl, 3 beta,5 alpha-Pgl, and 3 alpha,5 alpha-Pgl were considerably more potent for eliciting lordosis than P (14, 13.7, 9, and 4-fold, respectively) [3].
• A slow onset of action in DHP is a very important mechanism in preventing reflex tachycardia [4].

High impact information on Dpys

• In the present study, we recorded single-calcium channel activities from HMs using a cell-attached patch-clamp method and found four types of channels that could be discriminated based on kinetics, voltage dependency, DHP sensitivity, and single-channel conductances [5].
• Of the Ca2+ current activated at 0 mV from a holding potential of -70 mV, approximately one-half was omega-Aga-IVA (200 nM) sensitive, one-third was omega-CgTx (3 microM) sensitive, whereas only 6% was DHP (nimodipine; 10 microM) sensitive [6].
• alpha-[3H]Dihydropicrotoxinin (DHP) and [3H]diazepam binding proteins were solubilized from rat brain membranes with 1% Lubrol-Px [7].
• The deduced amino acid sequence reveals that the CRAM gene encodes a protein of 563 amino acids, shows 57% identity with dihydropyrimidinase, and shows 50-51% identity with CRMPs [8].
• In contrast, both cell lines exhibited DHP-resistant [Ca(2+)](i) increases in response to KCl [9].

Chemical compound and disease context of Dpys

• In a second study, the antiprogestin RU486 (5 mg, SC), injected 60 min before one of four selected progestins (alpha DHP, 3 alpha,5 alpha-Pgl, 3 alpha,5 beta-Pgl, and 3 beta,5 beta-Pgl), significantly inhibited their action on estrous behavior (lordosis and proceptivity) when tested at 60 and 120 min postinjection [3].
• It was concluded that DHP is a potent antithyroid compound of the thiouracil type with low general toxicity, since mammals can tolerate a level of intake sufficient to produce goitre in spite of iodine supplementation [10].

Biological context of Dpys

• A cDNA encoding dihydropyrimidinase has been isolated from a rat cDNA library [11].
• Pyrazolopyridines, such as etazolate (SQ 20009), enhance [3H]diazepam binding to a Lubrol-solubilized fraction that has specific binding sites for 3H benzodiazepines, [alpha-3H]dihydropicrotoxinin (DHP) and [3H]muscimol [12].
• DHPase catalyzed the reversible cyclization of 5,6-dihydrouracil (H2Ura) to N-carbamoyl-beta-alanine or 5,6-dihydrothymine (H2Thy) to N-carbamoyl-beta-aminoisobutyric acid [13].
• Coculture decreased SMC DHP-receptor levels under atmospheric pressure [14].
• The alpha1c subunit (DHP receptor) of the L-type Ca2+ channel is important for calcium homeostasis in cardiac muscle [15].

Anatomical context of Dpys

• CONCLUSIONS: Our results suggest that Ang II-induced contraction is dependent on extracellular calcium, and enhanced functional coupling of AT1 receptors and DHP-sensitive L-type calcium channels results in supersensitivity to Ang II in thoracic aorta isolated from diabetic rats [16].
• In this study, we report that the metabolism of clivorine, a tumorigenic otonecine type PA, by F344 rat liver microsomes results in DHP formation [17].
• Intact calf thymus DNA was also reacted with DHP and then digested by MN/SPD under the same conditions [1].
• The abundance of DHP receptors, determined by ligand binding, was two-fold greater in myocytes after 3 days in high Ca2+ [18].
• The uncovered R-type calcium current can account for part of the presynaptic Ca2+ current controlling neurotransmitter release at the mammalian neuromuscular junction whose activity is resistant to DHP-and omega-CTx-GVIA, and displays anomalous sensitivity to omega-Aga-IVA and omega-CTx-MVIIC [19].

Associations of Dpys with chemical compounds

• Although KCl elicited a prolonged elevation in [Ca(2+)](i), glucose triggered oscillations in [Ca(2+)](i.) Ca(v)1.2/dihydropyridine-insensitive (DHPi) cells and Ca(v)1.3/DHPi cells, and stable INS-1 cell lines expressing either DHP-insensitive Ca(v)1.2 or Ca(v)1.3 channels showed normal responses to glucose [9].
• These results provide evidence that etazolate, like pentobarbital, modulates benzodiazepine binding via the DHP-sensitive site of the benzodiazepine-GABA receptor-ionophore complex [12].
• In this study, the remaining adducts have been characterized as DHP-modified dinucleotides [1].
• Identification of the entire set of DHP-derived DNA adducts further validates the conclusion that riddelliine is a genotoxic carcinogen and enhances the applicability of these biomarkers for assessing carcinogenic risks from exposure to pyrrolizidine alkaloids [1].
• When incubations were conducted with clivorine in the presence of calf thymus DNA, eight DHP-derived DNA adducts were formed [17].

Other interactions of Dpys

• Although the three enzymes from rat liver have similar sizes, with apparent molecular weights of 218 000 for dihydropyrimidine dehydrogenase, 226 000 for dihydropyrimidinase, and 234 000 for NC beta A amidohydrolase, they are easily separated from each other [20].
• The analysis of enriched mitochondrial fractions identified 10 proteins including sodium/potassium-transporting ATPase, cofilin, dihydropyrimidinase, pyruvate kinase and voltage dependent anion channel 1 that were statistically significantly (P < 0.05) altered in Abeta-treated cultures [21].
• Ammonium ions supplemented in the diet and given by injection did not affect the activities of rat liver pyrimidine-metabolizing enzymes (dihydropyrimidine dehydrogenase, dihydropyrimidinase, beta-ureidopropionase, beta-alanine-oxoglutarate aminotransferase and D-3-aminoisobutyrate-pyruvate aminotransferase) [22].

Analytical, diagnostic and therapeutic context of Dpys

• Molecular cloning and sequencing of a cDNA encoding dihydropyrimidinase from the rat liver [11].
• Previously, (32)P-postlabeling HPLC was used to detect a set of eight DHP-derived adduct peaks from DNA modified both in vitro and in vivo [1].
• Northern blot analysis revealed that culturing cells in high Ca2+ produced 1.5-fold increase in mRNA levels for the DHP receptor [18].
• We have localized dihydropyridine (DHP-sensitive calcium channels in rat brain by in situ hybridization and immunohistochemistry [23].
• Tissue radiolabeled P4 and P4 metabolites (5 alpha-pregnane-3,20-dione, DHP; 20 alpha-hydroxy P4; 17 alpha-hydroxy P4, and hydroxylated DHP derivatives) were extracted and separated by thin-layer chromatography (TLC) [24].

References