Predicting idiopathic toxicity of cisplatin by a pharmacometabonomic approach

Kwon, Hyuk Nam; Kim, Mina; He, Wen; Kang, Sa-Ouk; Yang, Hye Jin; Choi, Myung Ja; Lee, Jun Young; Choi, Dalwoong; Park, In Suh; Suh, Young Ju; Hong, Soon‐Sun; Park, Sunghyouk

doi:10.1038/ki.2010.440

Cited by 49 publications

(33 citation statements)

References 61 publications

(74 reference statements)

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“…In the past decades, metabolomics has been applied in various research fields such as pharmaceutical and clinical research, food technology and microbiology28293031. In cisplatin nephrotoxicity, metabolomics has also been introduced since 2006323334353637. The focus of these researches is discovering biomarkers that could be used for the early diagnosis of renal toxicity.…”

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confidence: 99%

Renal Medulla is More Sensitive to Cisplatin than Cortex Revealed by Untargeted Mass Spectrometry-Based Metabolomics in Rats

Zhang

Chen

Huang

et al. 2017

Sci Rep

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Nephrotoxicity has long been the most severe and life-threatening side-effect of cisplatin, whose anticancer effect is therefore restricted. Previous pathological studies have shown that both renal cortex and medulla could be injured by cisplatin. Our TUNEL (terminal deoxynucleotidyl transferasemediated dUTP nick end-labeling) assay results further uncovered that medulla subjected more severe injury than cortex. In order to depict the underlying metabolic mechanism of spatial difference in response to cisplatin, in the present study, mass spectrometry-based untargeted metabolomics approach was applied to profile renal cortex and medulla metabolites of rat after receiving a single dose of cisplatin (2.5, 5 or 10 mg/kg). Eventually, 53 and 55 differential metabolites in cortex and medulla were screened out, respectively. Random forest, orthogonal partial least squares-discriminant analysis and metabolic cumulative fold change analysis revealed that metabolic changes in medulla were more obviously dose-dependent than those in cortex, which confirmed the conclusion that medulla was more sensitive to cisplatin exposure. Furthermore, 29 intermediates were recognized as the most contributive metabolites for the sensitivity difference. Metabolic pathways interrupted by cisplatin mainly included amino acid, energy, lipid, pyrimidine, purine, and creatine metabolism. Our findings provide new insight into the mechanism study of cisplatin-induced nephrotoxicity.Cisplatin [cis-diamminedichloroplatinum(II)] is an effective antineoplastic agent that was widely applied in the treatment of various types of solid tumors in the past several decades 1-3 . However, due to poor selectivity, cisplatin could cause neurotoxicity, nephrotoxicity, nausea and vomiting, and ototoxicity et al. in clinical [4][5][6][7][8][9][10] . As the principal excretory organ for cisplatin, kidney accumulates and retains platinum to a greater degree than other organs 11,12 . Therefore, nephrotoxicity has long been the most severe and life-threatening toxicity among these side-effects 13,14 . Statistics showed there were about 25-35% patients experienced a significant decline in renal function after receiving a single dose of cisplatin 13,15 . The declines manifested clinically as lower glomerular filtration rate, reduced serum magnesium and potassium levels et al. 13,16 . Research over the past few years has gained significant insights into the mechanisms regarding cisplatin nephrotoxicity, which mainly involved apoptosis, inflammation and oxidative stress et al. [17][18][19][20][21][22] . However, how the toxicity occurs and develops, and how various types of mechanisms are integrated to induce distinct kidney pathology, remain largely unknown.Metabolomics is an emerging -omics approach that could provide information of holistic and time-dependent metabolic variation in response to xenobiotic interventions 23,24 . At present, metabolomics analysis encompasses different strategies depending on the objective of study, namely target analysis of a group of c...

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confidence: 99%

Renal Medulla is More Sensitive to Cisplatin than Cortex Revealed by Untargeted Mass Spectrometry-Based Metabolomics in Rats

Zhang

Chen

Huang

et al. 2017

Sci Rep

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“…In particular, urine has been used extensively to study the mechanism of external stimuli (i.e. drugs or toxic insults) at most major target organs, such as the lung, kidney, liver, or heart (12)(13)(14)(15)(16)(17)(18). Still, metabolomics studies of DR effects have been very limited.…”

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confidence: 99%

Enhanced Phase II Detoxification Contributes to Beneficial Effects of Dietary Restriction as Revealed by Multi-platform Metabolomics Studies

Yang

et al. 2013

Molecular & Cellular Proteomics

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Dietary restriction (DR) has many beneficial effects, but the detailed metabolic mechanism remains largely unresolved. As diet is essentially related to metabolism, we investigated the metabolite profiles of urines from control and DR animals using NMR and LC/MS metabolomic approaches. Multivariate analysis presented distinctive metabolic profiles and marker signals from glucuronide and glycine conjugation pathways in the DR group. Broad profiling of the urine phase II metabolites with neutral loss scanning showed that levels of glucuronide and glycine conjugation metabolites were generally higher in the DR group. The up-regulation of phase II detoxification in the DR group was confirmed by mRNA and protein expression levels of uridinediphospho-glucuronosyltransferase and glycine-N-acyltransferase in actual liver tissues. Histopathology and serum biochemistry showed that DR was correlated with the beneficial effects of low levels of serum alanine transaminase and glycogen granules in liver. In addition, the Nuclear factor (erythroid-derived 2)-like 2 signaling pathway was shown to be up-regulated, providing a mechanistic clue regarding the enhanced phase II detoxification in liver tissue. Taken together, our metabolomic and biochemical studies provide a possible metabolic perspective for understanding the complex mechanism underlying the beneficial effects of DR. It has been known for more than 70 years that dietary restriction (DR) 1 can extend the life span and delay the onset of age-related diseases, based on an early rodent study showing such effects (1). However, not until the 1980s was DR recognized as a good model for studying the mechanism of or inhibitory measures for aging (2). So far, extensive studies employing model organisms such as yeasts, nematodes, fruit flies, and rodents have shown that DR has beneficial effects in most of the species studied (for a review, see Ref.3). Most notably, a recent 20-year-long study showed that monkeys, the species closest to humans, also benefit from DR similarly (4). Although there has not been (or could not have been) a systematic study on the effects of DR on the human life span, several longitudinal studies strongly suggest that changes in dietary intake can affect the life span and/or disease-associated marker values greatly (5-7).This inverse correlation between dietary intake and longterm health strongly indicates that DR's effects should involve metabolism, and that DR elicits the reorganization of metabolic pathways. It also seems quite natural that something we eat should affect the body's metabolism. Despite this seemingly straightforward relationship between diet and metabolism, the mechanisms underlying the beneficial effects of DR are anything but simple. Intensive efforts, spanning decades, to understand the mechanisms of DR have identified several genes that might mediate the effects of DR, such as mTOR, IGF-1, AMPK, and SIRT1 (for a review, see Ref. 8). Still, most of them are involved in early nutrient-sensing steps, and specific metabolic pathway...

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“…Kwon et al conducted a study on the nephrotoxicity of cisplatin in male Sprague-Dawley rats, which showed differences in response between different subgroups of animals. 53 In the pharmacometabonomic arm of the study, it was found that predose concentrations of allantoin, creatinine and succinate were higher in the subgroup resistant to nephrotoxicity, whilst 2-oxoglutarate was at a higher level in the group that was susceptible to nephrotoxicity. A leave-one-out analysis showed that the accuracy of predicting toxicity was 66%.…”

Section: Preclinical Pharmacometabonomics the Origin Of Preclinical Pmentioning

confidence: 95%

Pharmacometabonomics and personalized medicine

2013

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Background: Pharmacometabonomics is a new branch of science, first described in 2006 and defined as 'the prediction of the effects of a drug on the basis of a mathematical model of pre-dose metabolite profiles'. Pharmacometabonomics has been used to predict drug metabolism, pharmacokinetics (PK), drug safety and drug efficacy in both animals and humans and is complementary to both pharmacogenomics (PGx) and pharmacoproteomics. Methods: A literature review using the search terms pharmacometabonomics, pharmacometabolomics, pharmacometabonomics, pharmaco-metabolomics and the singular form of all those terms was conducted in October 2012 using PubMed and Web of Science. The review was updated until mid April 2013. Results: Since the original description of pharmacometabonomics in 2006, 21 original publications and eight reviews have emerged, covering a broad range of applications from the prediction of PK to the prediction of drug metabolism, efficacy and safety in humans and animals. Conclusions: Pharmacometabonomics promises to be an important new approach to the delivery of personalized medicine to improve both drug efficacy and safety for patients in the future. Pharmacometabonomics is particularly powerful as it is sensitive to both genetic and environmental factors such as diet, drug intake and most importantly, a person's microbiome. PGx is now over 50 years old and although it has not achieved as much as some hoped, it is starting to have important applications in personalized medicine. We predict that pharmacometabonomics will be equally important in the next few decades and will be both valuable in its own right and complementary to pharmacoproteomics and PGx.

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Predicting idiopathic toxicity of cisplatin by a pharmacometabonomic approach

Cited by 49 publications

References 61 publications

Renal Medulla is More Sensitive to Cisplatin than Cortex Revealed by Untargeted Mass Spectrometry-Based Metabolomics in Rats

Renal Medulla is More Sensitive to Cisplatin than Cortex Revealed by Untargeted Mass Spectrometry-Based Metabolomics in Rats

Enhanced Phase II Detoxification Contributes to Beneficial Effects of Dietary Restriction as Revealed by Multi-platform Metabolomics Studies

Pharmacometabonomics and personalized medicine

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