In-vitro and in-vivo functional observation studies to establish therapeutic potential of alpha-ketoglutarate against methotrexate induced liver injury

Background: Methotrexate (MTX) is widely used in chemotherapy but its associated hepatotoxicity is a major complication, limiting its use. This study evaluates possible therapeutic effect of oral alpha-ketoglutarate (AKG) supplementation against MTX-induced hepatotoxicity. Methods: HepG2 cells were...

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Autores principales:	Lalita Mehra, Aditi Bhattacharya, Harish Rawat, Amit Kumar, Abhinav Jaimini, Gaurav Mittal
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Methotrexate Oxidative stress Hepatotoxicity Alpha-ketoglutarate 99mTc-mebrofenin Gamma scintigraphy Medicine (General) R5-920 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/1542538085564ce485f36e1fdee8c6cd
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spelling	oai:doaj.org-article:1542538085564ce485f36e1fdee8c6cd2021-11-28T04:33:08ZIn-vitro and in-vivo functional observation studies to establish therapeutic potential of alpha-ketoglutarate against methotrexate induced liver injury2319-417010.1016/j.bj.2020.05.012https://doaj.org/article/1542538085564ce485f36e1fdee8c6cd2021-10-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2319417020300767https://doaj.org/toc/2319-4170Background: Methotrexate (MTX) is widely used in chemotherapy but its associated hepatotoxicity is a major complication, limiting its use. This study evaluates possible therapeutic effect of oral alpha-ketoglutarate (AKG) supplementation against MTX-induced hepatotoxicity. Methods: HepG2 cells were used to evaluate in-vitro cyto-protection conferred by AKG against MTX induced cytotoxicity. For in-vivo animal study, rats were divided into three groups. Group-I served as control. Group-II animals were administered single intraperitoneal injection of MTX (20 mg/kg/body weight), while Group-III received MTX as in group-II followed by oral AKG (2 gm/kg body weight) for 5 days. 99mTc-Mebrofenin hepatobiliary study was performed under a gamma camera to determine real time functional status of rats’ livers. Multiple parameters concerning hepatic mebrofenin uptake and excretion, including Tpeak and T1/2 peak in control and treated animals were determined. Biochemical analysis of the liver homogenate in terms of hepatic enzyme activities in serum, antioxidant status, tissue factor activity, tissue collagen content and histological analysis of the liver tissue were also done. Results: AKG supplementation significantly reversed MTX induced derangement in activities of serum liver enzymes [ALT and ALP (p = 0.003); AST (p = 0.005)], antioxidant status [LPO and GSH (p = 0.005); CAT (p = 0.004)], tissue factor activity (p = 0.005) and tissue collagen content (p = 0.005). Functional imaging confirmed that hepatic retention and fractional biliary excretion were significantly abnormal in MTX treated group (Tpeak: 234 s ± 40 s; T1/2 peak: 846sec ± 32sec) as compared to AKG supplemented group (Tpeak: 144 s ± 35sec; T1/2peak: 468sec ± 27sec). Hepatic extraction fraction (HEF) was 92.2 ± 1.8%, 48.7 ± 2.6% and 69.8 ± 4.3% in control, MTX and AKG supplemented rats respectively. Conclusion: 99mTc-mebrofenin imaging strongly suggests therapeutic action of AKG in protecting liver damage by MTX in rats. Functional imaging parameters correlated well with biochemical and histopathological findings.Lalita MehraAditi BhattacharyaHarish RawatAmit KumarAbhinav JaiminiGaurav MittalElsevierarticleMethotrexateOxidative stressHepatotoxicityAlpha-ketoglutarate99mTc-mebrofeninGamma scintigraphyMedicine (General)R5-920Biology (General)QH301-705.5ENBiomedical Journal, Vol 44, Iss 5, Pp 611-619 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Methotrexate Oxidative stress Hepatotoxicity Alpha-ketoglutarate 99mTc-mebrofenin Gamma scintigraphy Medicine (General) R5-920 Biology (General) QH301-705.5
spellingShingle	Methotrexate Oxidative stress Hepatotoxicity Alpha-ketoglutarate 99mTc-mebrofenin Gamma scintigraphy Medicine (General) R5-920 Biology (General) QH301-705.5 Lalita Mehra Aditi Bhattacharya Harish Rawat Amit Kumar Abhinav Jaimini Gaurav Mittal In-vitro and in-vivo functional observation studies to establish therapeutic potential of alpha-ketoglutarate against methotrexate induced liver injury
description	Background: Methotrexate (MTX) is widely used in chemotherapy but its associated hepatotoxicity is a major complication, limiting its use. This study evaluates possible therapeutic effect of oral alpha-ketoglutarate (AKG) supplementation against MTX-induced hepatotoxicity. Methods: HepG2 cells were used to evaluate in-vitro cyto-protection conferred by AKG against MTX induced cytotoxicity. For in-vivo animal study, rats were divided into three groups. Group-I served as control. Group-II animals were administered single intraperitoneal injection of MTX (20 mg/kg/body weight), while Group-III received MTX as in group-II followed by oral AKG (2 gm/kg body weight) for 5 days. 99mTc-Mebrofenin hepatobiliary study was performed under a gamma camera to determine real time functional status of rats’ livers. Multiple parameters concerning hepatic mebrofenin uptake and excretion, including Tpeak and T1/2 peak in control and treated animals were determined. Biochemical analysis of the liver homogenate in terms of hepatic enzyme activities in serum, antioxidant status, tissue factor activity, tissue collagen content and histological analysis of the liver tissue were also done. Results: AKG supplementation significantly reversed MTX induced derangement in activities of serum liver enzymes [ALT and ALP (p = 0.003); AST (p = 0.005)], antioxidant status [LPO and GSH (p = 0.005); CAT (p = 0.004)], tissue factor activity (p = 0.005) and tissue collagen content (p = 0.005). Functional imaging confirmed that hepatic retention and fractional biliary excretion were significantly abnormal in MTX treated group (Tpeak: 234 s ± 40 s; T1/2 peak: 846sec ± 32sec) as compared to AKG supplemented group (Tpeak: 144 s ± 35sec; T1/2peak: 468sec ± 27sec). Hepatic extraction fraction (HEF) was 92.2 ± 1.8%, 48.7 ± 2.6% and 69.8 ± 4.3% in control, MTX and AKG supplemented rats respectively. Conclusion: 99mTc-mebrofenin imaging strongly suggests therapeutic action of AKG in protecting liver damage by MTX in rats. Functional imaging parameters correlated well with biochemical and histopathological findings.
format	article
author	Lalita Mehra Aditi Bhattacharya Harish Rawat Amit Kumar Abhinav Jaimini Gaurav Mittal
author_facet	Lalita Mehra Aditi Bhattacharya Harish Rawat Amit Kumar Abhinav Jaimini Gaurav Mittal
author_sort	Lalita Mehra
title	In-vitro and in-vivo functional observation studies to establish therapeutic potential of alpha-ketoglutarate against methotrexate induced liver injury
title_short	In-vitro and in-vivo functional observation studies to establish therapeutic potential of alpha-ketoglutarate against methotrexate induced liver injury
title_full	In-vitro and in-vivo functional observation studies to establish therapeutic potential of alpha-ketoglutarate against methotrexate induced liver injury
title_fullStr	In-vitro and in-vivo functional observation studies to establish therapeutic potential of alpha-ketoglutarate against methotrexate induced liver injury
title_full_unstemmed	In-vitro and in-vivo functional observation studies to establish therapeutic potential of alpha-ketoglutarate against methotrexate induced liver injury
title_sort	in-vitro and in-vivo functional observation studies to establish therapeutic potential of alpha-ketoglutarate against methotrexate induced liver injury
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/1542538085564ce485f36e1fdee8c6cd
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In-vitro and in-vivo functional observation studies to establish therapeutic potential of alpha-ketoglutarate against methotrexate induced liver injury

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