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

Miyashita, Taishi; Kimura, Kento; Fukami, Tatsuki; Nakajima, Miki; Yokoi, Tsuyoshi

doi:10.1124/dmd.113.054478

Cited by 32 publications

(24 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…With direct toxicity, covalent protein binding via acyl-glucuronide may disrupt the normal physiologic function of a critical protein or some critical regulatory pathway that leads to cellular necrosis (Pirmohamed et al, 1996). Inflammation-mediated toxicity was investigated in a recent study, which showed that acyl-glucuronides induce inflammatory toxicity and cytotoxicity against CD14 + cells via the p38 mitogen-activated protein kinase pathway (Miyashita et al, 2014). In the case of diclofenac, it was previously demonstrated that the acylglucuronide can either bind directly to protein with displacement of the glucuronide group, or can rearrange to form a reactive imine intermediate that binds to proteins (Kretz-Rommel and Boelsterli, 1994).…”

Section: Introductionmentioning

confidence: 99%

Glucuronidation of Drugs and Drug-Induced Toxicity in HumanizedUDP-Glucuronosyltransferase 1Mice

et al. 2014

View full text Add to dashboard Cite

UDP-glucuronosyltransferases (UGTs) are phase II drug-metabolizing enzymes that catalyze glucuronidation of various drugs. Although experimental rodents are used in preclinical studies to predict glucuronidation and toxicity of drugs in humans, species differences in glucuronidation and drug-induced toxicity have been reported. Humanized UGT1 mice in which the original Ugt1 locus was disrupted and replaced with the human UGT1 locus (hUGT1 mice) were recently developed. In this study, acyl-glucuronidations of etodolac, diclofenac, and ibuprofen in liver microsomes of hUGT1 mice were examined and compared with those of humans and regular mice. The kinetics of etodolac, diclofenac, and ibuprofen acyl-glucuronidation in hUGT1 mice were almost comparable to those in humans, rather than in mice. We further investigated the hepatotoxicity of ibuprofen in hUGT1 mice and regular mice by measuring serum alanine amino transferase (ALT) levels. Because ALT levels were increased at 6 hours after dosing in hUGT1 mice and at 24 hours after dosing in regular mice, the onset pattern of ibuprofen-induced liver toxicity in hUGT1 mice was different from that in regular mice. These data suggest that hUGT1 mice can be valuable tools for understanding glucuronidations of drugs and druginduced toxicity in humans.

show abstract

Section: Introductionmentioning

confidence: 99%

Glucuronidation of Drugs and Drug-Induced Toxicity in HumanizedUDP-Glucuronosyltransferase 1Mice

et al. 2014

View full text Add to dashboard Cite

show abstract

“…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). Thus, these in vitro studies indicate that the toxicity of AGs remains controversial.…”

Section: Discussionmentioning

confidence: 97%

“…From our previous findings, AGs of warning and withdrawn drugs induced immune-and inflammation-related genes such as IL-6 and IL-8 in human PBMCs (Miyashita et al, 2014;Iwamura et al, 2015). Hence, the changes in the renal mRNA expression levels of immuneand inflammation-related genes were measured.…”

Section: Downloaded Frommentioning

confidence: 99%

“…Because of their electrophilic nature and ability to cause substitution reactions with nucleophilic groups in proteins or other macromolecules, AGs can covalently modify endogenous proteins and have been postulated to cause the adverse toxicity associated with carboxylic acid-containing drugs (Faed, 1984;Boelsterli, 2002). To assess the toxicity of AGs, several in vitro assay systems, such as stability assay by measuring half-lives in potassium phosphate buffer, peptide adducts assay, and immunostimulation assay, have been proposed (Wang et al, 2004;Sawamura et al, 2010;Jinno et al, 2013;Miyashita et al, 2014;Iwamura et al, 2015). However, the toxicity of AGs has remained controversial because direct evidence of in vivo AG toxicity has not been provided.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Iwamura

Watanabe

Akai

et al. 2016

Drug Metabolism and Disposition

View full text Add to dashboard Cite

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.

show abstract

“…9) It was therefore hypothesized that the trovafloxacin acyl-glucuronide was involved in the development of toxicity in the liver. Acyl-glucuronide-associated toxicity has been reported in vivo and in vitro ; 10,11) however, there are also reports showing that acyl-glucuronidation did not induce the cyto- and genotoxicity. 12) Microarray expression analysis is a promising tool to identify genes associated with a drug treatment.…”

Section: Introductionmentioning

confidence: 99%

Acyl-glucuronide as a Possible Cause of Trovafloxacin-Induced Liver Toxicity: Induction of Chemokine (C-X-C Motif) Ligand 2 by Trovafloxacin Acyl-glucuronide

Mitsugi

Sumida

Fujie

et al. 2016

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Summary UDP-glucuronosyltransferases (UGTs) catalyze glucuronidation of endogenous and exogenous compounds by transferring the glucuronic acid moiety of UDP-glucuronic acid to the substrates. While glucuronides are usually pharmacologically inactive, certain types of glucuronides, especially acyl-glucuronide, can exhibit the increased reactivity compared to the parent compounds. Trovafloxacin is an antibiotic that was withdrawn from the market relatively soon after its release due to the risk of hepatotoxicity. Trovafloxacin was mainly metabolized to its acyl-glucuronide; therefore, it was hypothesized that the acyl-glucuronide was involved in the development of hepatotoxicity. To investigate whether trovafloxacin acyl-glucuronide can be involved in the trovafloxacin-induced liver injury, in the present study, a cell-based UGT1A1-induced model was developed and the toxicity of trovafloxacin acyl-glucuronide was evaluated. The UGT1A1-induced cell model was developed by treating HepG2 cells with chrysin for 48 hours. We demonstrated for the first time that chemokine (C-X-C motif) ligand 2, a cytokine involved in drug-induced liver injury, was uniquely induced by trovafloxacin in the UGT1A1-induced HepG2 cells. While there are reports showing the less toxicity of acyl-glucuronides, certain kinds of acyl-glucuronide, including trovafloxacin acyl-glucuronide, can be associated with the development of toxic reactions in vitro and in vivo.

show abstract

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

Cited by 32 publications

References 25 publications

Glucuronidation of Drugs and Drug-Induced Toxicity in HumanizedUDP-Glucuronosyltransferase 1Mice

Glucuronidation of Drugs and Drug-Induced Toxicity in HumanizedUDP-Glucuronosyltransferase 1Mice

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

Acyl-glucuronide as a Possible Cause of Trovafloxacin-Induced Liver Toxicity: Induction of Chemokine (C-X-C Motif) Ligand 2 by Trovafloxacin Acyl-glucuronide

Contact Info

Product

Resources

About