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Gene Review

Dpys  -  dihydropyrimidinase

Rattus norvegicus

Synonyms: DHP, DHPase, Dihydropyrimidinase, Dihydropyrimidine amidohydrolase, Hydantoinase
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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


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


Analytical, diagnostic and therapeutic context of Dpys


  1. Identification of DNA adducts derived from riddelliine, a carcinogenic pyrrolizidine alkaloid. Chou, M.W., Jian, Y., Williams, L.D., Xia, Q., Churchwell, M., Doerge, D.R., Fu, P.P. Chem. Res. Toxicol. (2003) [Pubmed]
  2. The relationship between the concentration of the pyrrolizidine alkaloid monocrotaline and the pattern of metabolites released from the isolated liver. Yan, C.C., Huxtable, R.J. Toxicol. Appl. Pharmacol. (1995) [Pubmed]
  3. Ring A reduced progestins potently stimulate estrous behavior in rats: paradoxical effect through the progesterone receptor. Beyer, C., Gonzalez-Flores, O., Gonzalez-Mariscal, G. Physiol. Behav. (1995) [Pubmed]
  4. Differential time course of the vasodilator action of various calcium antagonists. van der Lee, R., Kam, K.L., Pfaffendorf, M., van Zwieten, P.A. Fundamental & clinical pharmacology. (1998) [Pubmed]
  5. Single-channel properties of four calcium channel types in rat motoneurons. Umemiya, M., Berger, A.J. J. Neurosci. (1995) [Pubmed]
  6. Properties and function of low- and high-voltage-activated Ca2+ channels in hypoglossal motoneurons. Umemiya, M., Berger, A.J. J. Neurosci. (1994) [Pubmed]
  7. Picrotoxinin and diazepam bind to two distinct proteins: further evidence that pentobarbital may act at the picrotoxinin site. Davis, W.C., Ticku, M.K. J. Neurosci. (1981) [Pubmed]
  8. Identification of CRAM, a novel unc-33 gene family protein that associates with CRMP3 and protein-tyrosine kinase(s) in the developing rat brain. Inatome, R., Tsujimura, T., Hitomi, T., Mitsui, N., Hermann, P., Kuroda, S., Yamamura, H., Yanagi, S. J. Biol. Chem. (2000) [Pubmed]
  9. Cav1.3 is preferentially coupled to glucose-induced [Ca2+]i oscillations in the pancreatic beta cell line INS-1. Liu, G., Hilliard, N., Hockerman, G.H. Mol. Pharmacol. (2004) [Pubmed]
  10. The goitrogen 3-hydroxy-4(1H)-pyridone, a ruminal metabolite from Leucaena leucocephala: effects in mice and rats. Hegarty, M.P., Lee, C.P., Christie, G.S., Court, R.D., Haydock, K.P. Aust. J. Biol. Sci. (1979) [Pubmed]
  11. Molecular cloning and sequencing of a cDNA encoding dihydropyrimidinase from the rat liver. Matsuda, K., Sakata, S., Kaneko, M., Hamajima, N., Nonaka, M., Sasaki, M., Tamaki, N. Biochim. Biophys. Acta (1996) [Pubmed]
  12. Molecular interactions of etazolate with benzodiazepine and picrotoxinin binding sites. Ticku, M.K., Davis, W.C. J. Neurochem. (1982) [Pubmed]
  13. Purification, characterization and inhibition of dihydropyrimidinase from rat liver. Kikugawa, M., Kaneko, M., Fujimoto-Sakata, S., Maeda, M., Kawasaki, K., Takagi, T., Tamaki, N. Eur. J. Biochem. (1994) [Pubmed]
  14. Chronic high pressure potentiates the antiproliferative effect and abolishes contractile phenotypic changes caused by endothelial cells in cocultured smooth muscle cells. Vouyouka, A.G., Salib, S.S., Cala, S., Marsh, J.D., Basson, M.D. J. Surg. Res. (2003) [Pubmed]
  15. Norepinephrine regulates the in vivo expression of the L-type calcium channel. Golden, K.L., Ren, J., Dean, A., Marsh, J.D. Mol. Cell. Biochem. (2002) [Pubmed]
  16. AT1 receptors and L-type calcium channels: functional coupling in supersensitivity to angiotensin II in diabetic rats. Arun, K.H., Kaul, C.L., Ramarao, P. Cardiovasc. Res. (2005) [Pubmed]
  17. Metabolic formation of DHP-derived DNA adducts from a representative otonecine type pyrrolizidine alkaloid clivorine and the extract of Ligularia hodgsonnii hook. Xia, Q., Chou, M.W., Lin, G., Fu, P.P. Chem. Res. Toxicol. (2004) [Pubmed]
  18. Expression of calcium channels in adult cardiac myocytes is regulated by calcium. Davidoff, A.J., Maki, T.M., Ellingsen, O., Marsh, J.D. J. Mol. Cell. Cardiol. (1997) [Pubmed]
  19. Antagonists-resistant calcium currents in rat embryo motoneurons. Magnelli, V., Baldelli, P., Carbone, E. Eur. J. Neurosci. (1998) [Pubmed]
  20. Pyrimidine catabolism: individual characterization of the three sequential enzymes with a new assay. Traut, T.W., Loechel, S. Biochemistry (1984) [Pubmed]
  21. Quantitative proteomic analysis of mitochondria from primary neuron cultures treated with amyloid beta peptide. Lovell, M.A., Xiong, S., Markesbery, W.R., Lynn, B.C. Neurochem. Res. (2005) [Pubmed]
  22. Effect of dietary protein on pyrimidine-metabolizing enzymes in rats. Kaneko, M., Fujimoto, S., Kikugawa, M., Kontani, Y., Tamaki, N. J. Nutr. Sci. Vitaminol. (1991) [Pubmed]
  23. Expression of dihydropyridine-sensitive brain calcium channels in the rat central nervous system. Chin, H., Smith, M.A., Kim, H.L., Kim, H. FEBS Lett. (1992) [Pubmed]
  24. Uterine progesterone metabolism during early pseudopregnancy in the rat. Redmond, A.F., Pepe, G.J. Biol. Reprod. (1986) [Pubmed]
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