Genotoxicity of Acyl Glucuronide Metabolites Formed from Clofibric Acid and Gemfibrozil: A Novel Role for Phase-II-Mediated Bioactivation in the Hepatocarcinogenicity of the Parent Aglycones?

Sallustio, Benedetta C.; Harkin, Louise A.; Mann, Maretta; Krivickas, Sara J.; Burcham, Philip

doi:10.1006/taap.1997.8322

Cited by 40 publications

(31 citation statements)

References 17 publications

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“…The comet assay is a unique assay method for assessing the genotoxicity of AG (Sallustio et al, 1997(Sallustio et al, , 2006Southwood et al, 2007). Thus, we investigated genotoxicity using the comet assay.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, it has been reported that electrophilic AG can covalently interact with nucleic acids. For example, clofibrate AG and gemfibrozil AG can form DNA adducts, resulting in genotoxicity that can be measured by the single-cell gel electrophoresis (comet) assay (Sallustio et al, 1997). Furthermore, probenecid and clofibric acid induced DNA damage in isolated hepatocytes and UDP-glucuronosyltransferase (UGT)-transfected HEK293 cells via a glucuronidation-dependent pathway (Sallustio et al, 2006;Southwood et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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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

et al. 2010

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ABSTRACT: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 that AG formation was related to the toxicity. In the present study, the cytotoxicity and genotoxicity of AGs were investigated. Human embryonic kidney (HEK) 293 cells stably expressing UDP-glucuronosyltransferase (UGT) 1A3 (HEK/UGT1A3) were constructed to assess the cytotoxicity of AGs, and HEK/UGT1A4 cells were also used as a negative reference. After exposure to nonsteroidal antiinflammatory drugs (NSAIDs) such as naproxen (1 mM), diclofenac (0.1 mM), ketoprofen (1 mM), or ibuprofen (1 mM) for 24 h, HEK/ UGT1A3 cells produced AG in a time-dependent manner. However, HEK/UGT1A4 cells hardly produced AG. The cytotoxicity of HEK/ UGT1A3 cells was not increased compared with that of HEK/ UGT1A4 cells. In addition, the AG formed in NSAID-treated human hepatocytes was decreased from one-third to one-ninth by treatment with (؊)-borneol, an inhibitor of acyl glucuronidation, but the cytotoxicity was increased. These results indicated that AG formation reflected the detoxification process in human hepatocytes. Furthermore, the possibility of genotoxicity from the AG formed in NSAID-treated HEK/UGT cells was investigated by the comet assay, and DNA damage was not detected in any HEK/UGT cell lines. In conclusion, the in vitro cytotoxic and genotoxic effects of the AGs of NSAIDs were investigated and AG was not found to be a causal factor in the toxicity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2010

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“…In another instance, DNA is a target for the acyl glucuronide conjugate of gemfibrozil. Incubations of gemfibrozil acyl glucuronide conjugate with DNA resulted in the formation of covalent adducts and mutagenesis [53].…”

Section: Toxicological Implicationsmentioning

confidence: 99%

Role and Clinical Consequences of HumanUDP‐Glucuronosyltransferases

Dalvie

Loi

2012

Encyclopedia of Drug Metabolism and Interactions

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Uridine 5′‐diphosphate‐glucuronosyltransferases (UGT) are a family of enzymes that catalyze the conjugation of various drugs and endogenous substances. UGTs contribute to multiple important physiologic functions in the body and serve as an important detoxification pathway for certain drugs. In addition to their abundance in the liver and kidneys, UGTs are also expressed in several other organs including the GI tract. Given their importance in the disposition of drugs and their ubiquitous nature, they have the potential to influence the pharmacokinetics and biological effects of drugs. In addition to detoxification, UGTs are also responsible in metabolically activating compounds to reactive metabolites such as the acyl glucuronides that have the potential to covalently bind to macromolecules and elicit deleterious effects. As the cytochrome P450s (CYPs), UGTs are also subject to genetic polymorphisms and drug‐drug interactions (DDIs), which can impact the clinical development of drugs. This chapter presents an overview of the role and clinical consequences of metabolism of drugs by UGT.

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“…It is interesting to note that both humans and nonhuman primates are refractory to hepatocellular carcinoma caused by PPAR␣ agonists (Reddy et al, 1980;Rao and Reddy, 1987;Ward et al, 1998;Klaunig et al, 2003;Hoivik et al, 2004), yet the mechanism behind the species-related difference of susceptibility to these drugs remains to be firmly established (Peters et al, 2000;Hoivik et al, 2004). Some metabolites of PPAR␣ agonists have been reported to cause toxicity and complex drug-drug interactions, underscoring the need for detailed metabolic studies of PPAR␣ agonists (Sallustio et al, 1997;Backman et al, 2002;Prueksaritanont et al, 2002;Shitara et al, 2004).…”

mentioning

confidence: 99%

Fenofibrate Metabolism in the Cynomolgus Monkey using Ultraperformance Liquid Chromatography-Quadrupole Time-of-Flight Mass Spectrometry-Based Metabolomics

Liu¹,

Patterson²,

Yang³

et al. 2009

Drug Metab Dispos

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ABSTRACT:Fenofibrate, widely used for the treatment of dyslipidemia, activates the nuclear receptor, peroxisome proliferator-activated receptor ␣. However, liver toxicity, including liver cancer, occurs in rodents treated with fibrate drugs. Marked species differences occur in response to fibrate drugs, especially between rodents and humans, the latter of which are resistant to fibrate-induced cancer. Fenofibrate metabolism, which also shows species differences, has not been fully determined in humans and surrogate primates. In the present study, the metabolism of fenofibrate was investigated in cynomolgus monkeys by ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOFMS)-based metabolomics. Urine samples were collected before and after oral doses of fenofibrate. The samples were analyzed in both positive-ion and negative-ion modes by UPLC-QTOFMS, and after data deconvolution, the resulting data matrices were subjected to multivariate data analysis. Pattern recognition was performed on the retention time, mass/charge ratio, and other metabolite-related variables. Synthesized or purchased authentic compounds were used for metabolite identification and structure elucidation by liquid chromatographytandem mass spectrometry. Several metabolites were identified, including fenofibric acid, reduced fenofibric acid, fenofibric acid ester glucuronide, reduced fenofibric acid ester glucuronide, and compound X. Another two metabolites (compound B and compound AR), not previously reported in other species, were characterized in cynomolgus monkeys. More importantly, previously unknown metabolites, fenofibric acid taurine conjugate and reduced fenofibric acid taurine conjugate were identified, revealing a previously unrecognized conjugation pathway for fenofibrate.

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Genotoxicity of Acyl Glucuronide Metabolites Formed from Clofibric Acid and Gemfibrozil: A Novel Role for Phase-II-Mediated Bioactivation in the Hepatocarcinogenicity of the Parent Aglycones?

Cited by 40 publications

References 17 publications

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

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

Role and Clinical Consequences of HumanUDP‐Glucuronosyltransferases

Fenofibrate Metabolism in the Cynomolgus Monkey using Ultraperformance Liquid Chromatography-Quadrupole Time-of-Flight Mass Spectrometry-Based Metabolomics

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