Oxidative stress potentiated by diallylsulfide, a selective CYP2E1 inhibitor, in isoniazid toxic effect on rat primary hepatocytes

Zhai, Qing; Lu, Sheng; Lin, Yang‐Wei; Yang, Qi; Yu, Bo

doi:10.1016/j.toxlet.2008.10.007

“…In line with these findings, Enriquez-Cortina et al reported that oxidative stress and inhibition of hepatic antioxidant activities were the key determinants of INH-induced hepatotoxicity (50). Additionally, the hepatic microsomal CYP450 system, mainly CYP2E1, is considered a central role player in the ROS generation pathway, either directly or as a by-product of its metabolic activities through the generation of reactive metabolites (51,52). As experimentally evident, our obtained results revealed that LPS augmented INH-induced CYP2E1 protein expression levels while repressing CYP2E1 gene expression.…”

Section: Discussionmentioning

confidence: 86%

Role of Inflammatory and Oxidative Stress, Cytochrome P450 2E1, and Bile Acid Disturbance in Rat Liver Injury Induced by Isoniazid and Lipopolysaccharide Cotreatment

Hassan

¹

,

Guo

²

,

Yousef

³

et al. 2016

Antimicrob Agents Chemother

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Isoniazid (INH), since its introduction in the year 1952, still serves as a frontline drug in tuberculosis treatment (1). Despite the fact that INH has been widely used as a first-line antitubercular agent (2, 3), its therapeutic value is usually accompanied by severe hepatotoxicity and lethal hepatic injury (4, 5). Although the pathophysiology of INH-induced liver injury might vary, the toxicity features of the drug, including hepatocellular steatosis, necrosis, and inflammatory infiltration, are nearly consistent (6, 7).Even though extensive studies expounding INH toxicity have been carried out, the exact mechanism of INH hepatotoxicity remains controversial. Among numerous established theories, an inflammatory stress theory has recently been widely used to explain the idiosyncrasy. One hypothesis is that inflammatory stress increases sensitivity to drug-induced liver injury (DILI) (8, 9). In this theory, an incidence of systemic inflammation might reduce the xenobiotic toxicity threshold, which could be easily accomplished by coadministration with an inflammatory agent (10), thus promoting drug toxicity. Lipopolysaccharide (LPS) is an outer cell wall membrane constituent of Gram-negative bacteria that has been comprehensively studied as an inflammatory agent with a major role in bacterial infections (11,12). Previous studies have suggested that LPS might intensify DILI (13-15), and, hence, a possible cornerstone role for LPS in INH-induced hepatotoxicity might be assumed.Oxidative stress, generated from the accumulation of reactive oxygen species (ROS), may be potentiated by different factors, including drugs and inflammation (16,17). In addition, oxidative stress plays a major role in several types of hepatic injury (18). Furthermore, with cytochrome P450 2E1 (CYP2E1) playing a major role in drug metabolism and the pathophysiology of DILI (19) and being considered a principal element in human susceptibility to chemical toxins (20), it plays a central part in oxidative stress, production of ROS, and hepatotoxic injury. Moreover, a previous report proposed that hepatic CYP2E1 plays a fundamental role in the propagation of INH-induced hepatotoxicity, mainly throughout ROS generation (21). Nevertheless, a full understanding of CYP2E1 as a major hepatotoxin-forming, catalyzing enzyme and its influence on INH-induced liver damage has not been completely achieved.Studies of the hepatotoxic mechanisms of INH were previously conducted using different animal models; however, results were accompanied by the absence of certain features of INH toxicity, i.e., delayed onset or inconsistency in severity compared to that in hu-

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“…Although DAS has a protective effect, 16 it is also known to cause toxicity at high concentration and when used for longer time. 17 Therefore, we performed a subsequent experiment using CYP2E1 siRNA to assess the specificity of DAS. Similar to the increase in oxidative stress by CYP2E1 siRNA alone (Figure 1b), it also caused significant cell death (Supplementary Figure S2C), suggesting that a basal level of CYP2E1 is required for cell survival.…”

Section: Resultsmentioning

confidence: 99%

“…DAS, a selective inhibitor of CYP2E1, is a food additive, and has been shown to be protective to immune cells, 16 could be a potential target for alcohol-induced immune suppression and neurotoxicity. However, as DAS could also be toxic, 17 novel chemical derivatives with relatively lower toxicity than DAS can be synthesized to use them as a therapeutic.…”

Section: Discussionmentioning

confidence: 99%

Regulation of cytochrome P450 2e1 expression by ethanol: role of oxidative stress-mediated pkc/jnk/sp1 pathway

Jin

¹

,

Ande

²

,

Kumar

³

et al. 2013

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CYP2E1 metabolizes ethanol leading to production of reactive oxygen species (ROS) and acetaldehyde, which are known to cause not only liver damage but also toxicity to other organs. However, the signaling pathways involved in CYP2E1 regulation by ethanol are not clear, especially in extra-hepatic cells. This study was designed to examine the role of CYP2E1 in ethanol-mediated oxidative stress and cytotoxicity, as well as signaling pathways by which ethanol regulates CYP2E1 in extra-hepatic cells. In this study, we used astrocytic and monocytic cell lines, because they are important cells in central nervous system . Our results showed that 100 mM ethanol significantly induced oxidative stress, apoptosis, and cell death at 24 h in the SVGA astrocytic cell line, which was rescued by a CYP2E1 selective inhibitor, diallyl sulfide (DAS), CYP2E1 siRNA, and antioxidants (vitamins C and E). Further, we showed that DAS and vitamin C abrogated ethanol-mediated (50 mℳ) induction of CYP2E1 at 6 h, as well as production of ROS at 2 h, suggesting the role of oxidative stress in ethanol-mediated induction of CYP2E1. We then investigated the role of the protein kinase C/c-Jun N-terminal kinase/specificity protein1 (PKC/JNK/SP1) pathway in oxidative stress-mediated CYP2E1 induction. Our results showed that staurosporine, a non-specific inhibitor of PKC, as well as specific PKCζ inhibitor and PKCζ siRNA, abolished ethanol-induced CYP2E1 expression. In addition, inhibitors of JNK (SP600125) and SP1 (mithramycin A) completely abrogated induction of CYP2E1 by ethanol in SVGA astrocytes. Subsequently, we showed that CYP2E1 is also responsible for ethanol-mediated oxidative stress and apoptotic cell death in U937 monocytic cell lines. Finally, our results showed that PKC/JNK/SP1 pathway is also involved in regulation of CYP2E1 in U937 cells. This study has clinical implications with respect to alcohol-associated neuroinflammatory toxicity among alcohol users.

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“…DAS, a selective inhibitor of CYP2E1, is a food additive, and has been shown to be protective to immune cells, 16 could be a potential target for alcohol-induced immune suppression and neurotoxicity. However, as DAS could also be toxic, 17 novel chemical derivatives with relatively lower toxicity than DAS can be synthesized to use them as a therapeutic. Cell culture and treatments.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Cytochrome P450 2E1 expression by ethanol: Role of oxidative stressmediated PKC/JNK/SP1 pathway

2013

J Bioequiv Availab

0

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CYP2E1 metabolizes ethanol leading to production of reactive oxygen species (ROS) and acetaldehyde, which are known to cause not only liver damage but also toxicity to other organs. However, the signaling pathways involved in CYP2E1 regulation by ethanol are not clear, especially in extra-hepatic cells. This study was designed to examine the role of CYP2E1 in ethanolmediated oxidative stress and cytotoxicity, as well as signaling pathways by which ethanol regulates CYP2E1 in extra-hepatic cells. In this study, we used astrocytic and monocytic cell lines, because they are important cells in central nervous system . Our results showed that 100 mM ethanol significantly induced oxidative stress, apoptosis, and cell death at 24 h in the SVGA astrocytic cell line, which was rescued by a CYP2E1 selective inhibitor, diallyl sulfide (DAS), CYP2E1 siRNA, and antioxidants (vitamins C and E). Further, we showed that DAS and vitamin C abrogated ethanol-mediated (50 mM) induction of CYP2E1 at 6 h, as well as production of ROS at 2 h, suggesting the role of oxidative stress in ethanol-mediated induction of CYP2E1. We then investigated the role of the protein kinase C/c-Jun N-terminal kinase/specificity protein1 (PKC/JNK/SP1) pathway in oxidative stress-mediated CYP2E1 induction. Our results showed that staurosporine, a non-specific inhibitor of PKC, as well as specific PKCf inhibitor and PKCf siRNA, abolished ethanol-induced CYP2E1 expression. In addition, inhibitors of JNK (SP600125) and SP1 (mithramycin A) completely abrogated induction of CYP2E1 by ethanol in SVGA astrocytes. Subsequently, we showed that CYP2E1 is also responsible for ethanol-mediated oxidative stress and apoptotic cell death in U937 monocytic cell lines. Finally, our results showed that PKC/JNK/SP1 pathway is also involved in regulation of CYP2E1 in U937 cells. This study has clinical implications with respect to alcohol-associated neuroinflammatory toxicity among alcohol users. 1 To a lesser extent, they are also involved in xenobiotic metabolism in other organs, such as intestine, brain, and kidney. CYP2E1 is known to metabolize ethanol in the liver, especially in chronic alcohol users; 2 however, the persistent use of alcohol and resulting alcohol metabolism is known to cause liver toxicity. 3The alcohol metabolism-mediated liver toxicity occurs through the formation of reactive oxygen species (ROS) and the reactive metabolite, acetaldehyde, which ultimately cause DNA damage and lipid and protein oxidations. 4 Low levels of alcohol in occasional or social mild-tomoderate drinkers are metabolized mainly by alcohol dehydrogenase (ADH), which also appears to cause oxidative stress-mediated liver toxicity.5 However, alcohol-inducible CYP2E1 also has an important role in alcohol metabolism and mediate liver impairment among variety of alcohol drinkers. 2Although the role of CYP2E1 in alcohol-mediated liver toxicity is well known, similar studies are limited in extra-hepatic cells, especially cells from the CNS. Results from previous studies have led to the s...

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Oxidative stress potentiated by diallylsulfide, a selective CYP2E1 inhibitor, in isoniazid toxic effect on rat primary hepatocytes

Cited by 25 publications

References 14 publications

Role of Inflammatory and Oxidative Stress, Cytochrome P450 2E1, and Bile Acid Disturbance in Rat Liver Injury Induced by Isoniazid and Lipopolysaccharide Cotreatment

Role of Inflammatory and Oxidative Stress, Cytochrome P450 2E1, and Bile Acid Disturbance in Rat Liver Injury Induced by Isoniazid and Lipopolysaccharide Cotreatment

Regulation of cytochrome P450 2e1 expression by ethanol: role of oxidative stress-mediated pkc/jnk/sp1 pathway

Regulation of Cytochrome P450 2E1 expression by ethanol: Role of oxidative stressmediated PKC/JNK/SP1 pathway

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