Comparative study of the binding characteristics to and inhibitory potencies towards PARP and in vivo antidiabetogenic potencies of taurine, 3-aminobenzamide and nicotinamide.
BACKGROUND
Poly(ADP-ribose) is a NAD+-requiring, DNA-repairing, enzyme playing a central role in pancreatic beta-cell death and in the development of endothelial dysfunction in humans and experimental animals. PARP activation is also relevant to the development of complications of diabetes. Hence, agents capable of inhibiting PARP may be useful in preventing the development of diabetes and in slowing down complications of diabetes.


METHODS
PARP inhibition was assessed with a colorimetric assay kit. Molecular docking studies on the active site of PARP were conducted using the crystalline structure of the enzyme available as Protein Data Bank Identification No. 1UK1. Type 2 diabetes was induced in male Sprague-Dawley rats with streptozotocin (STZ, 60 mg/kg, i.p.). The test compounds (3-aminobenzamide = 3-AB, nicotinamide = NIC, taurine = TAU) were given by the i.p. route 45 min before STZ at 2.4 mM/kg (all three compounds) or 1.2 and 3.6 mM/kg (only NIC and TAU). Blood samples were collected at 24 hr after STZ and processed for their plasma. The plasma samples were used to measure glucose, insulin, cholesterol, triglycerides, malondialdehyde, nitric oxide, and glutathione levels using reported methods.


RESULTS
3-AB, NIC and TAU were able to inhibit PARP, with the inhibitory potency order being 3-AB>NIC> or =TAU. Molecular docking studies at the active site of PARP showed 3-AB and NIC to interact with the binding site for the nicotinamide moiety of NAD+ and TAU to interact with the binding site for the adenine moiety of NAD+. While STZ-induced diabetes elevated all the experimental parameters examined and lowered the insulin output, a pretreatment with 3-AB, NIC or TAU reversed these trends to a significant extent. At a dose of 2.4 mm/kg, the protective effect decreased in the approximate order 3-AB>NIC> or =TAU. The attenuating actions of both NIC and TAU were dose-related except for the plasma lipids since NIC was without a significant effect at all doses tested.


CONCLUSIONS
At equal molar doses, 3-AB was generally more potent than either TAU or NIC as an antidiabetogenic agent, but the differences were not as dramatic as would have been predicted from their differences in PARP inhibitory potencies. NIC and TAU demonstrated dose-related effects, which in the case of TAU were only evident at doses > or =2.4 mM/kg. The present results also suggest that in the case of NIC and TAU an increase in dose will enhance the magnitude of their attenuating actions on diabetes-related biochemical alterations to that achieved with a stronger PARP inhibitor such as 3-AB. Hence, dosing will play a critical role in clinical studies assessing the merits of NIC and TAU as diabetes-preventing agents.
Pandya
Kashyap G
KG
Department of Pharmaceutical Sciences, St, John's University, College of Pharmacy and Allied Health Professions, 8000 Utopia Parkway, Jamaica, New York 11439, USA. kashyap1983@yahoo.com
Patel
Maulik R
MR
Lau-Cam
Cesar A
CA
D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D020134:Catalytic Domain; D002784:Cholesterol / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000517:prevention & control*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D005978:Glutathione / Q000097:blood; D006801:Humans; D007328:Insulin / Q000097:blood; D008297:Male; D008958:Models, Molecular; D018696:Neuroprotective Agents / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D009536:Niacinamide / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin / Q000494:pharmacology; D013654:Taurine / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D014280:Triglycerides / Q000097:blood; D014803:Vitamin B Complex / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use
D001549:Benzamides; D001786:Blood Glucose; D004791:Enzyme Inhibitors; D007328:Insulin; D018696:Neuroprotective Agents; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D014280:Triglycerides; D014803:Vitamin B Complex; D013654:Taurine; D009536:Niacinamide; D013311:Streptozocin; C025160:3-aminobenzamide; D002784:Cholesterol; D011065:Poly(ADP-ribose) Polymerases; D005978:Glutathione
Lancet. 2004 Mar 20;363(9413):925-31
15043959
Mutat Res. 2002 Dec;512(2-3):121-34
12464347
Biochem Biophys Res Commun. 1993 Mar 15;191(2):759-65
8461028
Expert Rev Mol Med. 2005 Mar 15;7(4):1-20
15836799
Free Radic Biol Med. 2009 Jul 1;47(1):13-26
19362586
Diabetologia. 1993 Jun;36(6):574-6
8335182
Free Radic Biol Med. 1988;5(2):113-24
3075947
Metabolism. 2000 Apr;49(4):427-31
10778863
Circulation. 2004 Apr 20;109(15):1877-85
15037530
Pharmacol Res. 2005 Feb;51(2):117-23
15629256
Pharmacol Res. 2000 May;41(5):533-7
10753552
Methods Enzymol. 1978;52:302-10
672633
J Biol Chem. 1982 Jun 10;257(11):6084-8
6281256
Can J Physiol Pharmacol. 2009 Feb;87(2):91-9
19234572
Arch Biochem Biophys. 1959 May;82(1):70-7
13650640
Free Radic Biol Med. 2008 Mar 15;44(6):972-81
17976390
Br J Pharmacol. 1998 Mar;123(6):1089-96
9559891
Diabetologia. 2000 Nov;43(11):1337-45
11126400
Scand J Clin Lab Invest. 1960;12(4):402-7
13738785
Gen Pharmacol. 1997 Feb;28(2):257-63
9013204
J Pharmacol Exp Ther. 1983 Dec;227(3):749-54
6655568
Nat Med. 1999 Mar;5(3):269-70
10086377
J Pharmacol Exp Ther. 2007 Jan;320(1):458-64
17021258
Mutat Res. 2010 Jan 5;683(1-2):84-90
19887075
Nat Med. 2001 Jan;7(1):108-13
11135624
Biochem Pharmacol. 1979 Sep 15;28(18):2807-11
159055
Diabetes. 2003 Jul;52(7):1683-8
12829633
Biochem Biophys Res Commun. 1990 Dec 31;173(3):932-9
2176495
Cardiovasc Res. 1997 Nov;36(2):205-15
9463632
Physiol Res. 2001;50(6):537-46
11829314
J Biomed Sci. 2004 Jul-Aug;11(4):472-81
15153782
Diabetes. 1991 Sep;40(9):1141-5
1834504
Med Mol Morphol. 2005 Jun;38(2):84-91
15944815
Ann N Y Acad Sci. 1993 Nov 30;696:333-41
8109840
J Med Chem. 2004 Aug 12;47(17):4151-4
15293985
Biochem J. 1988 Nov 15;256(1):251-5
2851980
J Biol Chem. 2005 Jul 8;280(27):25313-22
15795231
Cardiovasc Drug Rev. 2007 Fall;25(3):235-60
17919258
Exp Toxicol Pathol. 2004 Dec;56(3):189-94
15625788
Biochem Med Metab Biol. 1990 Feb;43(1):1-9
2310608
Circ Res. 2001 Oct 12;89(8):684-91
11597991
Indian J Med Res. 1992 Jun;96:176-81
1512041
Biol Pharm Bull. 1993 Oct;16(10):970-2
8287047
Pharmacol Rev. 2002 Sep;54(3):375-429
12223530
Res Commun Chem Pathol Pharmacol. 1990 Jul;69(1):17-32
2145620
Yakugaku Zasshi. 1992 Nov;112(11):773-91
1484345
J Mol Endocrinol. 1999 Feb;22(1):65-70
9924181
FASEB J. 2003 Aug;17(11):1514-6
12824290
Diabetes Res Clin Pract. 2006 Mar;71(3):320-33
16233932
Diabetologia. 2004 Oct;47(10):1831-7
15502919
Neurosci Lett. 2004 Feb 6;356(1):45-8
14746898
Arch Med Res. 2007 Apr;38(3):276-83
17350476
Eur Rev Med Pharmacol Sci. 2005 Nov-Dec;9(6):361-7
16479741
Am J Physiol. 1995 Sep;269(3 Pt 2):F429-38
7573492
Comp Biochem Physiol A Mol Integr Physiol. 2003 Aug;135(4):539-47
12890544
Br J Pharmacol. 2001 Jul;133(6):909-19
11454665
Nat Med. 1999 Mar;5(3):314-9
10086388
Acta Diabetol. 2000 Mar;37(1):33-9
10928234
Diabetes. 2003 Aug;52(8):1994-9
12882915
Biochem Pharmacol. 1984 Sep 15;33(18):2835-8
6383406
Recent Pat Anticancer Drug Discov. 2006 Jan;1(1):39-53
18221025
FEBS Lett. 1988 Nov 7;239(2):295-8
2846360