Research Article


DOI :10.26650/IstanbulJPharm.2022.1136288   IUP :10.26650/IstanbulJPharm.2022.1136288    Full Text (PDF)

Gene expression profiles for apoptotic and necrotic pathways during Amanita phalloides intoxication in mice

Selim KarahanZehra AtlıErtuğrul KayaFeride ÖzdemirMehmet BoğaSevcan İzgi

Background and Aims: Amanita phalloides is the deadliest toxic mushroom in the world and causes death from acute liver failure. α-amanitin (α-AMA), the most potent toxin, inhibits RNA polymerase II in hepatocytes, stops protein synthesis, and causes hepatotoxicity. However, the information about the mechanisms underlying hepatotoxicity caused by α-AMA is quite inadequate. This study aims to reveal the complex necrotic and apoptotic mechanisms occurring in mouse hepatocytes depending on A. phalloides exposure time in vivo. Methods: BALB-c male mice were divided into 5 groups (n=7): control, α-AMA-2, α-AMA-12, α-AMA-72, and α-AMA-96 groups. A poisoning model was created by oral administration of A. phalloides mushroom extract containing 10 mg/kg of α-AMA to mice and they were sacrificed after 2, 12, 72, and 96 h. Then, TNF-α, Bax, caspase-3, and Bcl-2 gene expression levels in liver tissues were examined by the RT-qPCR method. Time-dependent damage to liver tissues was also evaluated histopathologically. Results: RT-qPCR results showed that proinflammatory cytokine TNF-α mRNA expression levels increased in mouse liver tissues at 2 and 12 h after A. phalloides administration compared among the groups. Bax mRNA expression levels increased in the 12 and 72 h after A. phalloides ingestion. It was observed that caspase-3 mRNA expression levels increased in the 72 and 96 h groups compared among the groups, while Bcl-2 mRNA expression levels decreased in the 72 and 96 h groups. Conclusion: Our findings showed that necrotic mechanisms develop in the early period after A. phalloides mushroom poisoning, and then apoptotic mechanisms are effective. In conclusion, understanding the mechanisms of A. phalloides-induced hepatotoxicity will provide important information for new treatment strategies to be developed.


PDF View

References

  • Alldredge B, C. R., Ernst M, Guglielmo B, Jacobson P, Kradjan, WA, & Williams, BR. (2012). Koda-Kimble and Young’s applied therapeutics: The clinical use of drugs (K. W Ed. 10th edition ed.): Lippincott Williams & Wilkins. google scholar
  • Angioi, A., Floris, M., Lepori, N., Bianco, P., Cabiddu, G., & Pani, A. (2021). Extensive proximal tubular necrosis without recovery following the ingestion of Amanita phalloides: a case report. Journal of nephrology, 34(6), 2137-2140. doi:https://10.1007/s40620-021-01018-w google scholar
  • Arima, Y., Hirota, T., Bronner, C., Mousli, M., Fujiwara, T., Niwa, S.-i., . . . Saya, H. (2004). Down-regulation of nuclear protein ICBP90 by p53/p21Cip1/WAF1-dependent DNA-damage checkpoint signals contributes to cell cycle arrest at G1/S transition. Genes to Cells, 9(2), 131-142. doi:https://doi.org/10.1111/j.1356-9597.2004.00710.x google scholar
  • Arima, Y., Nitta, M., Kuninaka, S., Zhang, D., Fujiwara, T., Taya, Y., . . . Saya, H. (2005). Transcriptional blockade induces p53-depen-dent apoptosis associated with translocation of p53 to mitochondria. Journal of Biological Chemistry, 280(19), 19166-19176. doi:https://10.1074/jbc.M410691200 google scholar
  • Barbosa, I. A., Machado, N. G., Skildum, A. J., Scott, P. M., & Oliveira, P. J. (2012). Mitochondrial remodeling in cancer metabolism and survival: potential for new therapies. Biochimica et Biophysica Acta, 1826(1), 238-254. doi:https://10.1016/j.bbcan.2012.04.005 google scholar
  • Becker, C. E., Tong, T. G., Boerner, U., Roe, R. L., Sco, T. A., MacQuar-rie, M. B., & Bartter, F. (1976). Diagnosis and treatment of Amanita phalloides-type mushroom poisoning: use of thioctic acid. Western Journal of Medicine, 125(2), 100-109. google scholar
  • Enjalbert, F., Rapior, S., Nouguier-Soulé, J., Guillon, S., Amouroux, N., & Cabot, C. (2002). Treatment of amatoxin poisoning: 20-year retrospective analysis. Journal of Clinical Toxicology, 40(6), 715-757. doi:https://10.1081/clt-120014646 google scholar
  • Escudie, L., Francoz, C., Vinel, J. P, Moucari, R., Cournot, M., Paradis, V., . . . Durand, F. (2007). Amanita phalloides poisoning: reassessment of prognostic factors and indications for emergency liver transplantation. Journal of Hepatology, 46(3), 466-473. doi:https://10.1016/j.jhep.2006.10.013 google scholar
  • Faulstich, H., Talas, A., & Wellhöner, H. H. (1985). Toxicokinetics of labeled amatoxins in the dog. Archives of Toxicology, 56(3), 190194. doi:https://10.1007/bf00333425 google scholar
  • Fineschi, V., Di Paolo, M., & Centini, F. (1996). Histological criteria for diagnosis of amanita phalloides poisoning. Journal of Forensic Sciences, 41(3), 429-432. google scholar
  • Ganzert, M., Felgenhauer, N., & Zilker, T. (2005). Indication of liver transplantation following amatoxin intoxication. Journal of Hepatology, 42(2), 202-209. doi:https://10.1016/j.jhep.2004.10.023 google scholar
  • Garcia, J., Costa, V. M., Carvalho, A. T., Silvestre, R., Duarte, J. A., Dourado, D. F., . . . Carvalho, F. (2015). A breakthrough on Amanita phalloides poisoning: an effective antidotal effect by polymyxin B. Archives of Toxicology, 89(12), 2305-2323. doi:https://10.1007/ s00204-015-1582-x google scholar
  • Jan, M. A., Siddiqui, T. S., Ahmed, N., Ul Haq, I., & Khan, Z. (2008). Mushroom poisoning in children: clinical presentation and outcome. Journal of Ayub Medical College Abbottabad, 20(2), 99-101. Karlson-Stiber, C., & Persson, H. (2003). Cytotoxic fungi--an overview. Toxicon, 42(4), 339-349. doi:https://10.1016/s0041-0101(03)00238-1 google scholar
  • Kaya E, H. M., Karahan S, Bayram S, Yaykaşlı KO, Sürmen MG. (2012). Thermostability of Alpha Amanitin in Water and Methanol. European Journal of Basic Medical Sciences, 2(4), 106-111. doi:https:// doi.org/10.21601/ejbms/9189 google scholar
  • Kaya, E., Karahan, S., Bayram, R., Yaykasli, K. O., Colakoglu, S., & Saritas, A. (2015). Amatoxin and phallotoxin concentration in Amanita phalloides spores and tissues. Toxicology and Industrial Health, 31(12), 1172-1177. doi:https://10.1177/0748233713491809 google scholar
  • Kaya, E., Surmen, M. G., Yaykasli, K. O., Karahan, S., Oktay, M., Turan, H., . . . Erdem, H. (2014). Dermal absorption and toxicity of alpha amanitin in mice. Cutaneous and Ocular Toxicology, 33(2), 154-160. doi:10.3109/15569527.2013.802697 google scholar
  • Kaya, E., Yilmaz, I., Admis, O., Oktay, M., Bayram, R., Bakirci, S., . . . Colakoglu, S. (2016). Effects of erdosteine on alpha amanitin-induced hepatotoxicity in mice. Toxin Reviews, 35(1-2), 4-9. doi:htt ps://10.1080/15569543.2016.1178146 google scholar
  • Kaya, E., Yilmaz, I., Sinirlioglu, Z. A., Karahan, S., Bayram, R., Yaykasli, K. O., . . . Severoglu, Z. (2013). Amanitin and phallotoxin concentration in Amanita phalloides var. alba mushroom. Toxicon, 76, 225-233. doi:https://10.1016/j.toxicon.2013.10.008 google scholar
  • Leist, M., Gantner, F., Naumann, H., Bluethmann, H., Vogt, K., Brige-lius-Flohe, R., . . . Wendel, A. (1997). Tumor necrosis factor-induced apoptosis during the poisoning of mice with hepatotoxins. Gastroenterology, 112(3), 923-934. doi:https://10.1053/gast.1997. v112.pm9041255 google scholar
  • Li, Y., Xi, Y., Tao, G., Xu, G., Yang, Z., Fu, X., . . . Jiang, T. (2020). Sirtuin 1 activation alleviates primary biliary cholangitis via the blocking of the NF-kB signaling pathway. International Immunopharmacology, 83, 106386. doi:https://10.1016/j.intimp.2020.106386 google scholar
  • Lindell, T. J., Weinberg, F., Morris, P. W., Roeder, R. G., & Rutter, W. J. (1970). Specific inhibition of nuclear RNA polymerase II by alpha-amanitin. Science, 170(3956), 447-449. doi:https://10.1126/ science.170.3956.447 google scholar
  • Magdalan, J., Ostrowska, A., Piotrowska, A., Gomutkiewicz, A., Podhorska-Okotow, M., Patrzatek, D., . . . Dziegiel, P (2010). Benzylpenicillin, acetylcysteine and silibinin as antidotes in human hepatocytes intoxicated with alpha-amanitin. Experimental and Toxicologic Pathology, 62(4), 367-373. doi:https://10.1016/j. etp.2009.05.003 google scholar
  • Magdalan, J., Ostrowska, A., Piotrowska, A., Izykowska, I., Nowak, M., Gomutkiewicz, A., . . . Dziegiel, P (2010). alpha-Amanitin induced apoptosis in primary cultured dog hepatocytes. Folia Histochemica et Cytobiologica, 48(1), 58-62. doi:https://10.2478/ v10042-010-0010-6 google scholar
  • Magdalan, J., Piotrowska, A., Gomutkiewicz, A., Sozanski, T,, Podhorska-Okotow, M., Szelag, A., & Dziegiel, P (2011). Ben-zylpenicyllin and acetylcysteine protection from a-amanitin-induced apoptosis in human hepatocyte cultures. Experimental and Toxicologic Pathology, 63(4), 311-315. doi:https://10.1016/j. etp.2010.02.004 google scholar
  • McIlwain, D. R., Berger, T., & Mak, T. W. (2013). Caspase functions in cell death and disease. Cold Spring Harbor perspectives in biology, 5(4), a008656-a008656. doi:https://10.1101/cshperspect.a008656 Park, R., Choi, W. G., Lee, M. S., Cho, Y. Y., Lee, J. Y., Kang, H. C., . . . Lee, H. S. (2021). Pharmacokinetics of a-amanitin in mice using liquid chromatography-high resolution mass spectrometry and in vitro drug-drug interaction potentials. Journal of Toxicology and Environmental Health, Part A, 84(20), 821-835. doi:htt ps://10.1080/15287394.2021.1944942 google scholar
  • Pislar, A., Sabotic, J., Slenc, J., Brzin, J., & Kos, J. (2016). Cytotoxic L-amino-acid oxidases from Amanita phalloides and Clitocybe geotropa induce caspase-dependent apoptosis. Cell Death Discovery, 2(1), 16021. doi:https://10.1038/cddiscovery.2016.21 google scholar
  • Schmittgen, T. D., & Livak, K. J. (2008). Analyzing real-time PCR data by the comparative C(T) method. Nature Protocols, 3(6), 1101-1108. doi:https://10.1038/nprot.2008.73 google scholar
  • Serne, E. H., Toorians, A. W., Gietema, J. A., Bronsveld, W., Haags-ma, E. B., & Mulder, P. O. (1996). Amanita phalloides, a potentially lethal mushroom: its clinical presentation and therapeutic options. Netherlands Journal of Medicine, 49(1), 19-23. doi:htt ps://10.1016/0300-2977(95)00096-8 google scholar
  • Smith, M. R., & Davis, R. L. (2016). Mycetismus: a review. Gastroenterology Report (Oxford), 4(2), 107-112. doi:https://10.1093/gastro/ gov062 google scholar
  • Tiegs, G., & Horst, A. K. (2022). TNF in the liver: targeting a central player in inflammation. Seminars in Immunopathology, 44(4), 445- 459. doi:10.1007/s00281-022-00910-2 google scholar
  • Tong, T. C., Hernandez, M., Richardson, W. H., 3rd, Betten, D. P., Favata, M., Riffenburgh, R. H., . . . Tanen, D. A. (2007). Comparative treatment of alpha-amanitin poisoning with N-acetylcys-teine, benzylpenicillin, cimetidine, thioctic acid, and silybin in a murine model. Annals of Emergency Medicine, 50(3), 282-288. doi:https://10.1016/j.annemergmed.2006.12.015 google scholar
  • Vetter, J. (1998). Toxins of Amanita phalloides. Toxicon, 36(1), 1324. doi:https://10.1016/s0041-0101(97)00074-3 google scholar
  • Wang, M., Chen, Y., Guo, Z., Yang, C., Qi, J., Fu, Y., . . . Wang, Y. (2018). Changes in the mitochondrial proteome in human hepatocytes in response to alpha-amanitin hepatotoxicity. Toxicon, 156, 34-40. doi:https://10.1016/j.toxicon.2018.11.002 google scholar
  • Wieland, T. (1983). The toxic peptides from Amanita mushrooms. International Journal of Peptide Research, 22(3), 257-276. doi:https: //10.1111/j.1399-3011.1983.tb02093.x google scholar
  • Wieland, T., & Faulstich, H. (1978). Amatoxins, phallotoxins, phal-lolysin, and antamanide: the biologically active components of poisonous Amanita mushrooms. CRC Critical Reviews in Biochemistry, 5(3), 185-260. doi:https://10.3109/10409237809149870 google scholar
  • Yilmaz, I., Ermis, F., Akata, I., & Kaya, E. (2015). A Case Study: What Doses of Amanita phalloides and Amatoxins Are Lethal to Humans? Wilderness & Environmental Medicine, 26(4), 491-496. doi:https://10.1016/j.wem.2015.08.002 google scholar
  • Zhang, C., Wang, C., Tang, S., Sun, Y., Zhao, D., Zhang, S., . . . Xiao, X. (2013). TNFR1/TNF-a and mitochondria interrelated signaling pathway mediates quinocetone-induced apoptosis in HepG2 cells. Food and Chemical Toxicology, 62, 825-838. doi:https://doi. org/10.1016/j.fct.2013.10.022 google scholar
  • Zhao, J., Cao, M., Zhang, J., Sun, Q., Chen, Q., & Yang, Z. R. (2006). Pathological effects of the mushroom toxin alpha-amanitin on BALB/c mice. Peptides, 27(12), 3047-3052. doi:https://10.1016/j. peptides.2006.08.015 google scholar
  • Zhou, H. Q., Liu, W., Wang, J., Huang, Y. Q., Li, P. Y., Zhu, Y., . . . Zhao, Y. L. (2017). Paeoniflorin attenuates ANIT-induced cholestasis by inhibiting apoptosis in vivo via mitochondria-dependent pathway. Biomedicine & Pharmacotherapy, 89, 696-704. doi:https://10.1016/j. biopha.2017.02.084 google scholar

Citations

Copy and paste a formatted citation or use one of the options to export in your chosen format


EXPORT



APA

Karahan, S., Atlı, Z., Kaya, E., Özdemir, F., Boğa, M., & İzgi, S. (2022). Gene expression profiles for apoptotic and necrotic pathways during Amanita phalloides intoxication in mice. İstanbul Journal of Pharmacy, 52(3), 281-288. https://doi.org/10.26650/IstanbulJPharm.2022.1136288


AMA

Karahan S, Atlı Z, Kaya E, Özdemir F, Boğa M, İzgi S. Gene expression profiles for apoptotic and necrotic pathways during Amanita phalloides intoxication in mice. İstanbul Journal of Pharmacy. 2022;52(3):281-288. https://doi.org/10.26650/IstanbulJPharm.2022.1136288


ABNT

Karahan, S.; Atlı, Z.; Kaya, E.; Özdemir, F.; Boğa, M.; İzgi, S. Gene expression profiles for apoptotic and necrotic pathways during Amanita phalloides intoxication in mice. İstanbul Journal of Pharmacy, [Publisher Location], v. 52, n. 3, p. 281-288, 2022.


Chicago: Author-Date Style

Karahan, Selim, and Zehra Atlı and Ertuğrul Kaya and Feride Özdemir and Mehmet Boğa and Sevcan İzgi. 2022. “Gene expression profiles for apoptotic and necrotic pathways during Amanita phalloides intoxication in mice.” İstanbul Journal of Pharmacy 52, no. 3: 281-288. https://doi.org/10.26650/IstanbulJPharm.2022.1136288


Chicago: Humanities Style

Karahan, Selim, and Zehra Atlı and Ertuğrul Kaya and Feride Özdemir and Mehmet Boğa and Sevcan İzgi. Gene expression profiles for apoptotic and necrotic pathways during Amanita phalloides intoxication in mice.” İstanbul Journal of Pharmacy 52, no. 3 (Feb. 2023): 281-288. https://doi.org/10.26650/IstanbulJPharm.2022.1136288


Harvard: Australian Style

Karahan, S & Atlı, Z & Kaya, E & Özdemir, F & Boğa, M & İzgi, S 2022, 'Gene expression profiles for apoptotic and necrotic pathways during Amanita phalloides intoxication in mice', İstanbul Journal of Pharmacy, vol. 52, no. 3, pp. 281-288, viewed 1 Feb. 2023, https://doi.org/10.26650/IstanbulJPharm.2022.1136288


Harvard: Author-Date Style

Karahan, S. and Atlı, Z. and Kaya, E. and Özdemir, F. and Boğa, M. and İzgi, S. (2022) ‘Gene expression profiles for apoptotic and necrotic pathways during Amanita phalloides intoxication in mice’, İstanbul Journal of Pharmacy, 52(3), pp. 281-288. https://doi.org/10.26650/IstanbulJPharm.2022.1136288 (1 Feb. 2023).


MLA

Karahan, Selim, and Zehra Atlı and Ertuğrul Kaya and Feride Özdemir and Mehmet Boğa and Sevcan İzgi. Gene expression profiles for apoptotic and necrotic pathways during Amanita phalloides intoxication in mice.” İstanbul Journal of Pharmacy, vol. 52, no. 3, 2022, pp. 281-288. [Database Container], https://doi.org/10.26650/IstanbulJPharm.2022.1136288


Vancouver

Karahan S, Atlı Z, Kaya E, Özdemir F, Boğa M, İzgi S. Gene expression profiles for apoptotic and necrotic pathways during Amanita phalloides intoxication in mice. İstanbul Journal of Pharmacy [Internet]. 1 Feb. 2023 [cited 1 Feb. 2023];52(3):281-288. Available from: https://doi.org/10.26650/IstanbulJPharm.2022.1136288 doi: 10.26650/IstanbulJPharm.2022.1136288


ISNAD

Karahan, Selim - Atlı, Zehra - Kaya, Ertuğrul - Özdemir, Feride - Boğa, Mehmet - İzgi, Sevcan. Gene expression profiles for apoptotic and necrotic pathways during Amanita phalloides intoxication in mice”. İstanbul Journal of Pharmacy 52/3 (Feb. 2023): 281-288. https://doi.org/10.26650/IstanbulJPharm.2022.1136288



TIMELINE


Submitted27.06.2022
Accepted28.09.2022
Published Online30.12.2022

LICENCE


Attribution-NonCommercial (CC BY-NC)

This license lets others remix, tweak, and build upon your work non-commercially, and although their new works must also acknowledge you and be non-commercial, they don’t have to license their derivative works on the same terms.


SHARE




Istanbul University Press aims to contribute to the dissemination of ever growing scientific knowledge through publication of high quality scientific journals and books in accordance with the international publishing standards and ethics. Istanbul University Press follows an open access, non-commercial, scholarly publishing.