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Arsenic induced alteration in Mrp-1 like activity leads to zebrafish hepatocyte apoptosis: The cellular GSH connection.
Environ Toxicol Pharmacol. 2020 May 26; 79:103427.ET

Abstract

Multidrug-resistance protein-1 facilitates the efflux of arsenic conjugated with reduced glutathione nonetheless; the relation between Mrp-1 ATPase activity and cellular GSH levels is contentious. To study this, Mrp-1-ATPase activity was measured in 5 μM arsenic trioxide exposed zebrafish hepatocytes (ZFH) and correlated with intracellular GSH levels. Alongside, mrp-1 gene expression as well as Mrp-1 protein level was also monitored. Diverse mode of Mrp-1 inhibition was reflected from differential level of Km and Vmax of Mrp-1 at different time points. 3 h post-arsenic treatment demonstrated non-competitive inhibition. At 6 h, there was significant increase in Km and ZFH death, suggesting reduced binding affinity of Mrp-1 for ATP. Increased caspase-9-cytochromeC-ATP levels (putative apoptosome), reinforced ZFH apoptosis. The increase in Vmax coupled with reduced substrate affinity of Mrp-1 suggests malfunctioning in arsenic- tolerance mechanisms. We posit the triggering glutathione level regulate arsenic tolerance in ZFH. Irreversible impairment of ATP binding to Mrp-1 culminates in arsenic-induced ZFH apoptosis.

Authors+Show Affiliations

Immunobiology Laboratory, Department of Zoology, University of Delhi, Delhi 110007, India. Electronic address: ray.atish@gmail.com.Immunobiology Laboratory, Department of Zoology, University of Delhi, Delhi 110007, India. Electronic address: shelly.g341@gmail.com.Natural Product Chemistry Group, CSTD, CSIR North East Institute of Science & Technology, Jorhat 785006, India; National Institute of Pharmaceutical Education and Research, Guwahati 781125, India. Electronic address: roysonali2005@gmail.com.Immunobiology Laboratory, Department of Zoology, University of Delhi, Delhi 110007, India; Faculty of Life Sciences & Biotechnology, South Asian University, New Delhi 110 021, India. Electronic address: shibnath1@yahoo.co.in.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32470611

Citation

Ray, Atish, et al. "Arsenic Induced Alteration in Mrp-1 Like Activity Leads to Zebrafish Hepatocyte Apoptosis: the Cellular GSH Connection." Environmental Toxicology and Pharmacology, vol. 79, 2020, p. 103427.
Ray A, Shelly A, Roy S, et al. Arsenic induced alteration in Mrp-1 like activity leads to zebrafish hepatocyte apoptosis: The cellular GSH connection. Environ Toxicol Pharmacol. 2020;79:103427.
Ray, A., Shelly, A., Roy, S., & Mazumder, S. (2020). Arsenic induced alteration in Mrp-1 like activity leads to zebrafish hepatocyte apoptosis: The cellular GSH connection. Environmental Toxicology and Pharmacology, 79, 103427. https://doi.org/10.1016/j.etap.2020.103427
Ray A, et al. Arsenic Induced Alteration in Mrp-1 Like Activity Leads to Zebrafish Hepatocyte Apoptosis: the Cellular GSH Connection. Environ Toxicol Pharmacol. 2020 May 26;79:103427. PubMed PMID: 32470611.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Arsenic induced alteration in Mrp-1 like activity leads to zebrafish hepatocyte apoptosis: The cellular GSH connection. AU - Ray,Atish, AU - Shelly,Asha, AU - Roy,Sonali, AU - Mazumder,Shibnath, Y1 - 2020/05/26/ PY - 2019/11/14/received PY - 2020/03/19/revised PY - 2020/05/24/accepted PY - 2020/5/30/pubmed PY - 2020/5/30/medline PY - 2020/5/30/entrez KW - Apoptosis KW - Arsenic KW - GSH KW - Mrp-1 KW - Zebrafish hepatocytes SP - 103427 EP - 103427 JF - Environmental toxicology and pharmacology JO - Environ. Toxicol. Pharmacol. VL - 79 N2 - Multidrug-resistance protein-1 facilitates the efflux of arsenic conjugated with reduced glutathione nonetheless; the relation between Mrp-1 ATPase activity and cellular GSH levels is contentious. To study this, Mrp-1-ATPase activity was measured in 5 μM arsenic trioxide exposed zebrafish hepatocytes (ZFH) and correlated with intracellular GSH levels. Alongside, mrp-1 gene expression as well as Mrp-1 protein level was also monitored. Diverse mode of Mrp-1 inhibition was reflected from differential level of Km and Vmax of Mrp-1 at different time points. 3 h post-arsenic treatment demonstrated non-competitive inhibition. At 6 h, there was significant increase in Km and ZFH death, suggesting reduced binding affinity of Mrp-1 for ATP. Increased caspase-9-cytochromeC-ATP levels (putative apoptosome), reinforced ZFH apoptosis. The increase in Vmax coupled with reduced substrate affinity of Mrp-1 suggests malfunctioning in arsenic- tolerance mechanisms. We posit the triggering glutathione level regulate arsenic tolerance in ZFH. Irreversible impairment of ATP binding to Mrp-1 culminates in arsenic-induced ZFH apoptosis. SN - 1872-7077 UR - https://www.unboundmedicine.com/medline/citation/32470611/Arsenic_induced_alteration_in_Mrp-1_like_activity_leads_to_zebrafish_hepatocyte_apoptosis:_the_cellular_GSH_connection L2 - https://linkinghub.elsevier.com/retrieve/pii/S1382-6689(20)30103-4 DB - PRIME DP - Unbound Medicine ER -
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