Toxicological Evaluation of Acyl Glucuronides of Nonsteroidal Anti-Inflammatory Drugs Using Human Embryonic Kidney 293 Cells Stably Expressing Human UDP-Glucuronosyltransferase and Human Hepatocytes

Koga, Toshitaka; Fujiwara, Ryoichi; Nakajima, Miki; Yokoi, Tsuyoshi

doi:10.1124/dmd.110.035600

Cited by 41 publications

(25 citation statements)

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“…Although there is increasing evidence that AGs form drug-protein adducts due to their chemical reactivity (Wang et al, 2001;Horng and Benet, 2013), cytotoxicity and genotoxicity of AGs have not been observed in vitro (Koga et al, 2011). Conversely, the AGs of withdrawn drugs and warning drugs that have idiosyncratic drug toxicity risks, such as zomepirac and diclofenac, induced the mRNA expression levels of immune-and inflammation-related genes in human PBMCs (Miyashita et al, 2014;Iwamura et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…In human hepatocytes, the AGs of nonsteroidal anti-inflammatory drugs (diclofenac, naproxen, ketoprofen, and ibuprofen) were rapidly excreted and did not accumulate in the cell (Koga et al, 2011). ZP-AG is immediately exported from the liver into blood rather than bile because excretion of ZP and its metabolites into bile is a minor route in humans and laboratory animals (Grindel et al, 1980).…”

Section: Downloaded Frommentioning

confidence: 99%

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Zomepirac Acyl Glucuronide Is Responsible for Zomepirac-Induced Acute Kidney Injury in Mice

Iwamura

Watanabe

Akai

et al. 2016

Drug Metabolism and Disposition

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Glucuronidation, an important phase II metabolic route, is generally considered to be a detoxification pathway. However, acyl glucuronides (AGs) have been implicated in the toxicity of carboxylic acid drugs due to their electrophilic reactivity. Zomepirac (ZP) was withdrawn from the market because of adverse effects such as renal toxicity. Although ZP is mainly metabolized to acyl glucuronide (ZP-AG) by UDP-glucuronosyltransferase, the role of ZP-AG in renal toxicity is unknown. In this study, we established a ZP-induced kidney injury mouse model by pretreatment with tri-o-tolyl phosphate (TOTP), a nonselective esterase inhibitor, and L-buthionine-(S,R)-sulfoximine (BSO), a glutathione synthesis inhibitor. The role of ZP-AG in renal toxicity was investigated using this model. The model showed significant increases in blood urea nitrogen (BUN) and creatinine (CRE), but not alanine aminotransferase. The ZP-AG concentrations were elevated by cotreatment with TOTP in the plasma and liver and especially in the kidney. The ZP-AG concentrations in the kidney correlated with values for BUN and CRE. Upon histopathological examination, vacuoles and infiltration of mononuclear cells were observed in the model mouse. In addition to immune-related responses, oxidative stress markers, such as the glutathione/ disulfide glutathione ratio and malondialdehyde levels, were different in the mouse model. The suppression of ZP-induced kidney injury by tempol, an antioxidant agent, suggested the involvement of oxidative stress in ZP-induced kidney injury. This is the first study to demonstrate that AG accumulation in the kidney by TOTP and BSO treatment could explain renal toxicity and to show the in vivo toxicological potential of AGs.

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Section: Discussionmentioning

confidence: 99%

Section: Downloaded Frommentioning

confidence: 99%

Zomepirac Acyl Glucuronide Is Responsible for Zomepirac-Induced Acute Kidney Injury in Mice

Iwamura

Watanabe

Akai

et al. 2016

Drug Metabolism and Disposition

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“…It is well known that AGs are characterized by their electrophilic reactivity, and this reactivity is implicated in a wide range of adverse drug effects, including drug hypersensitivity reactions and cellular toxicity (Ritter, 2000). We previously revealed that the AGs of various NSAIDs, such as naproxen, diclofenac, ketoprofen, and ibuprofen, showed no direct cytotoxicity and genotoxicity in human hepatocytes and cells stably expressing human UGTs (Koga et al, 2011). Therefore, in this study, we investigated whether the AGs exert toxicity through inflammation- dmd.aspetjournals.org related responses.…”

Section: Discussionmentioning

confidence: 99%

“…We previously revealed that the NSAID AGs that were produced in the cells are efficiently released from the cells into the culture medium (Koga et al, 2011). Thus, the effect of AGs was evaluated by exposing the AGs to the outside of the cells, i.e., the culture medium.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, there is increasing evidence that the formation of drug-protein adducts is involved in idiosyncratic reactions. However, we previously reported that the AGs of naproxen, diclofenac, ketoprofen, and ibuprofen do not lead to cytotoxicity or genotoxicity in HEK/UGT cells and human hepatocytes (Koga et al, 2011). Therefore, it is necessary to elucidate the possibility of immune-and/or inflammation-mediated toxicity to clarify the toxicity of AG.…”

Section: Introductionmentioning

confidence: 99%

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Evaluation and Mechanistic Analysis of the Cytotoxicity of the Acyl Glucuronide of Nonsteroidal Anti-Inflammatory Drugs

et al. 2013

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The chemical reactivity of acyl glucuronide (AG) has been thought to be associated with the toxic properties of drugs containing carboxylic acid moieties, but there has been no direct evidence showing that AG formation is related to the observed toxicity. In the present study, the cytotoxicity of AGs, especially that associated with the inflammatory response, was investigated. The changes in the mRNA and protein expression levels of interleukin 8 (IL-8) and monocyte chemoattractant protein (MCP)-1 induced by the treatment of human peripheral blood mononuclear cells (PBMCs) with diclofenac (Dic), probenecid (Pro), tolmetin (Tol), ibuprofen (Ibu), naproxen (Nap), and their AGs were investigated by real-time reverse transcription polymerase chain reaction, and the viabilities of CD3+, CD14+, and CD19+ cells were measured by flow cytometry. Treatment with Dic-AG, Pro-AG, and Tol-AG significantly increased the expression levels of IL-8 and MCP-1. In addition, Dic-AG, Pro-AG, and Tol-AG significantly decreased the viability of CD14+ cells. Of these three AGs, Dic-AG showed the most potent changes, followed by Tol-AG and Pro-AG. Treatment with Ibu-AG and Nap-AG affected neither the expression levels of IL-8 and MCP-1 nor the viability of CD14+ cells. None of the drugs affected the CD3+ and CD19+ cell populations. Dic-AG increased the phosphorylation of p38 mitogen-activated protein (MAP) kinase and c-Jun N-terminal kinase (JNK)1/2. The pretreatment of peripheral blood mononuclear cells (PBMCs) with SB203580 (p38 inhibitor) significantly suppressed the Dic-AG-induced expression of inflammatory factors and cytotoxicity of CD14+ cells. In conclusion, AGs induce inflammatory responses and cytotoxicity against CD14+ cells via the p38 MAPK pathway. These factors may be useful biomarkers for evaluating the toxicity of AGs.

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Biotransformation

Eaton,

Cui

2023

Patty's Toxicology

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Biotransformation—or the process by which the body changes the chemical structure of an exogenous chemical—is an essential component in the development of toxic responses to chemicals found in the workplace and general environment. There are hundreds of biotransformation enzymes that act on chemicals to change their chemical structure within the body. Many of these biotransformation enzymes (often called “drug‐metabolizing enzymes,” or DMEs) also play essential roles in the formation and elimination of important endogenous biomolecules, such as steroid hormones, neurotransmitters, and other signaling molecules. However, a subset of these enzymes appears to exist primarily for the purposes of detoxifying exogenous chemicals (xenobiotics). Because most of these enzymes are not essential to life, genetic polymorphisms are common and can impart large differences in susceptibility to certain chemicals found in our workplace, diet, or general environment. This chapter discusses the large multi‐gene families of enzymes that are involved in oxidation, reduction, hydrolysis, and conjugation of xenobiotics. Although the purpose of biotransformation processes is to facilitate both the detoxication and elimination of xenobiotics from the body, it often happens that short‐lived, reactive intermediates are formed in the process, and these may be more toxic than the parent molecule. Understanding the pathways of biotransformation, and how these pathways can contribute to both acute and chronic toxic effects of xenobiotics, is an important part of the field of toxicology as it pertains to workplace and environmental exposures to toxic substances.

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Toxicological Evaluation of Acyl Glucuronides of Nonsteroidal Anti-Inflammatory Drugs Using Human Embryonic Kidney 293 Cells Stably Expressing Human UDP-Glucuronosyltransferase and Human Hepatocytes

Cited by 41 publications

References 34 publications

Zomepirac Acyl Glucuronide Is Responsible for Zomepirac-Induced Acute Kidney Injury in Mice

Zomepirac Acyl Glucuronide Is Responsible for Zomepirac-Induced Acute Kidney Injury in Mice

Evaluation and Mechanistic Analysis of the Cytotoxicity of the Acyl Glucuronide of Nonsteroidal Anti-Inflammatory Drugs

Biotransformation

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