Cytoprotective Effect of Podophyllum hexandrum Against Gamma Radiation is Mediated via Hemopoietic System Stimulation and Up-Regulation of Heme-oxygenase-1 and the Prosurvival Multidomain Protein Bcl-2

Abstract

The radioprotective effect of a hydroalcoholic extracted material (REC-2000) from the rhizome of Podophyllum hexandrum was studied in mice exposed to lethal γ radiation (10 Gy). The extract (REC-2000) was found to restore the hemoglobin content (14.73 ± 0.33) and total leukocyte count (TLC) (4166.66 ± 0.02) in lethally (10 Gy) γ-irradiated mice on the 15th day in comparison to the radiation control mice. The hemoglobin content of the drug + radiation group was observed to be significantly (21.25%) higher than the radiation control group on the 10th day. Similarly, the TLC was significantly increased (83.33 times) in the drug + radiation group as compared to a radiation (10 Gy) only group on the 10th day. Enhanced expression of heme-oxygenase-1 and Bcl-2 protein observed by Western blotting further supports the observation of hemopoietic recovery in irradiated mice. These findings indicate that the bioactive constituents present in REC-2000 exert the radioprotective effect by modulating the hemopoietic system.

Keywords

Podophyllum hexandrum Himalayan Mayapple lethal ionizing radiation hemopoietic system radioprotection heme-oxygenase

References

Maunch P , Constine L , Greenberger J , Knospe W , Sullival J , Deeg HJ . Hemopoietic stem cell compartment: acute and late effects of radiation therapy and chemotherapy. Int J Radiat Oncol Biol Phys. 1995;31:1319-1339.

Uma Devi P . Normal tissue protection in cancer therapy: progress and prospects. Acta Oncol. 1998;37:247-252.

Samarth RM , Goyal PK , Kumar A . Radioprotective effects of Mentha piperita. J Med Aromatic Plant Sci. 2001;22/23:91-97.

Block MH . Panaplasia. In: Text-Atlas of Hematology. Philadelphia: Lea and Febiger; 1976:259-259.

Hoffbrand AV , Petitt JE . Essential Haematology. 3rd ed. London: Blackwell Science; 2000:1-437.

Arora R , Gupta D , Chawla R , et al. Radioprotection by plant products: present status and future prospects. Phytother Res. 2005;19:1-22.

Sharma A , Haksar A , Chawla R , et al. Zingiber officinale Rosc. modulates gamma radiation-induced conditioned taste aversion. Pharmacol Biochem Behav. 2005;81:864-870.

Mittal A , Pathania V , Agarwal PK , et al. Influence of Podophyllum hexandrum on endogenous antioxidant defense system in mice: possible role in radioprotection. J Ethnopharmacol. 2001;76: 253-262.

Kamil WM , Dewick PM . Biosynthetic relationship of aryltetralactone lignans to dibenzylbutyrolactone lignans. Phytochemistry. 1986;25:2093-2102.

10.

Gupta D , Arora R , Garg AP , Goel HC . Radiation-induced damage to mitochondria and its modification by Podophyllum hexandrum Royale in HepG2 cells. Mol Cell Biochem. 2003;247: 25-40.

11.

Schmid W . Chemical mutagen testing on in vivo somatic mammalian cell. Agents Actions. 1973;3:77-85.

12.

Chaubey RC , Bhilwade HN , Joshi B , Chauhan PS . Studies on the migration of micronucleated erythrocytes from bone marrow to peripheral blood in irradiated Swiss mice. Int J Radiat Biol. 1993;63:239-245.

13.

Bradford MM . A rapid and sensitive method for the quantification of microgram quantities of protein utilizing the principle of protein dye binding. Analyt Biochem. 1976;72:248-254.

14.

Walker JM . The Protein Protocols Handbook. Totowa, NJ: Humana; 1996.

15.

Samali A , Cotter TG . Heat shock proteins increase resistance to apoptosis. Exp Cell Res. 1996;223:163-170.

16.

Goel HC , Prasad J , Singh S , et al. Radioprotection by a herbal preparation of Hippophae rhamnoides, RH-3, against whole body lethal irradiation in mice. Phytomedicine. 2002;9:15-25.

17.

Cassarett A . Radiation Biology. Englewood Cliffs, NJ: Prentice Hall; 1968.

18.

Cherdyntseva N , Shishkina A , Butorin I , Hironobu M , Polina G , Kagiya TV . Effect of tocopherol-monoglucoside (TMG), a water-soluble glycosylated derivate of vitamin E, on hematopoietic recovery in irradiated mice. J Radiat Res. 2005;46:37-41.

19.

Jagetia GC , Baliga MS . Syzygium cumini (jamun) reduces the radiation-induced damage in the cultured human peripheral blood lymphocytes: a preliminary study. Toxicol Lett. 2002; 132:19-25.

20.

Jagetia GC , Venkatesh P , Baliga MS . Evaluation of radioprotective effect of Aegle marmelos (L.) Correa in the cultured human peripheral blood lymphocytes exposed to different doses of γ-radiation: a micronucleus study. Mutagenesis. 2003;18:387-393.

21.

Sunila ES , Kuttan G . Protective effect of Thuja occidentalis against radiation-induced toxicity in mice. Integrat Cancer Ther. 2005;4:322-328.

22.

Sarge K , Murphy SP , Moromoto RI . Activation of heat shock transcription by HSF-1 involves oligomerization, acquisition of DNA binding activity, and nuclear localization and can occur in the absence of stress. Mol Cell Biol. 1993;13:1392-1407.

23.

Lock M , Tanguy RN . Increased HSF activation in muscles with a high constitutive HSP-70 expression. Cell Stress Chaperone. 1996;3:189-196.

24.

Maines MD . Haem Oxygenase: Clinical Applications and Functions. Boca Raton, FL: CRC; 1992.

25.

Otterbein LE , Sylvester SL , Choi AMK . Hemoglobin provides protection against lethal endotoxemia in rats: the role of heme oxygenase-1. Am J Resp Cell Mol Biol. 1995;13:595-601.

26.

Maines MD . Heme oxygenase: function, multiplicity, regulatory mechanisms and clinical applications. Fed Am Soc Exp Biol. 1998;2:2557-2568.

27.

Keyse SM , Tyrrell RM . Heme oxygenase is the major 32kDa protein induced in human skin fibroblasts by UVA radiation, hydrogen peroxide and sodium arsenide. Proc Natl Acad Sci U S A. 1989;86:99-103.

28.

Martin D , Rojo AI , Salinas M . Regulation of heme oxygenase-1 expression through the phosphatidylinositol 3-kinase/AKT pathway and the Nrf2 transcription factor in response to the antioxidant phytochemical carnosol. J Biol Chem. 2004;279: 8919-8929.

29.

Balogun E , Hoque M , Gong P . Curcumin activates the heme oxygenase-1 gene via regulation of Nrf2 and the antioxidantresponsive element. Biochem J. 2002;371:887-895.

30.

Goodsell DS . The molecular perspective: Bcl-2 and apoptosis. Stem Cells. 2002;20:355-356.

31.

Arora R , Chawla R , Puri SC , et al. Radioprotective activity of low altitude Podophyllum hexandrum. J Environ Pathol Toxicol Oncol. 2005;24:253-269.

32.

Chawla R , Arora Rajesh , Kumar R , et al. Antioxidant activities of fractionated extracts of high altitude Podophyllum hexandrum in radiation protection. Mol Cell Biochem. 2005;273:193-208.

33.

Chawla R , Arora R , Sagar RK , et al. 3-O-β-D-galactopyranoside of quercetin as an active principle from high-altitude Podophyllum hexandrum and evaluation of its radioprotective properties. Z Naturforschung. 2005;60c:728-738.

34.

Sagar RK , Chawla R , Arora R , et al. Protection of hematopoietic system by Podophyllum hexandrum. Planta Medica. 2006;71:1-7.