3,4-Dehydrodebrisoquine, a Novel Debrisoquine Metabolite Formed from 4-Hydroxydebrisoquine That Affects the CYP2D6 Metabolic Ratio

Zhen, Yujie; Slanař, Ondřej; Krausz, Kristopher W.; Chen, Chi; Slavík, Josef; McPhail, Kerry L.; Zabriskie, T. Mark; Perlı́k, F; Gonzalez, Frank J.; Idle, Jeffrey R.

doi:10.1124/dmd.105.008920

Cited by 15 publications

(12 citation statements)

References 38 publications

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“…The importance of metabolomics as a priority research area is reflected in the National Institutes of Health Roadmap for Medical Research wherein it is named as a new pathway of discovery initiative (6). This powerful platform has been used in drug development, screening and metabolism (7) and to identify novel biomarkers of exposure (8), effect (9) and disease (10). …”

Section: Introductionmentioning

confidence: 99%

Radiation Metabolomics. 2. Dose- and Time-Dependent Urinary Excretion of Deaminated Purines and Pyrimidines after Sublethal Gamma-Radiation Exposure in Mice

et al. 2009

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Gamma-radiation exposure of humans is a major public health concern as the threat of terrorism and potential hostile use of radiological devices increases worldwide. We report here the effects of sublethal γ-radiation exposure on the mouse urinary metabolome determined using ultra-performance liquid chromatography-coupled time-of-flight mass spectrometry-based metabolomics. Five urinary biomarkers of sublethal radiation exposure that were statistically significantly elevated during the first 24 h after exposure to doses ranging from 1 to 3 Gy were unequivocally identified by tandem mass spectrometry. These are deaminated purine and pyrimidine derivatives, namely, thymidine, 2′-deoxyuridine, 2′-deoxyxanthosine, xanthine and xanthosine. Furthermore, the aminopyrimidine 2′-deoxycytidine appeared to display reduced urinary excretion at 2 and 3 Gy. The elevated biomarkers displayed a time-dependent excretion, peaking in urine at 8–12 h but returning to baseline by 36 h after exposure. It is proposed that 2′-deoxyuridine and 2′-deoxyxanthosine arise as a result of γ irradiation by nitrosative deamination of 2′-deoxycytidine and 2′-deoxyguanosine, respectively, and that this further leads to increased synthesis of thymidine, xanthine and xanthosine. The urinary excretion of deaminated purines and pyrimidines, at the expense of aminopurines and aminopyrimidines, appears to form the core of the urinary radiation metabolomic signature of mice exposed to sublethal doses of ionizing radiation.

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Section: Introductionmentioning

confidence: 99%

Radiation Metabolomics. 2. Dose- and Time-Dependent Urinary Excretion of Deaminated Purines and Pyrimidines after Sublethal Gamma-Radiation Exposure in Mice

et al. 2009

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“…Over the last decade, highly sensitive and specific analytical techniques such as LC/MS/MS, high resolution quadrupole-time-of-flight (Q-Tof) mass spectrometry, and LC/NMR have been widely applied to the study of drug metabolism. Not surprisingly, this has led to the recent discovery of a number of novel metabolites (Jaggi et al, 2002;Miao et al, 2005;Chang et al, 2006;Endo et al, 2007) and, in some cases, to the discovery of novel metabolic pathways (Tang et al, 2003;Yin et al, 2003;Zhen et al, 2006). Although many studies have been conducted on ␤-lapachone (ARQ 501), there have been no previous reports on its metabolism either in animals or in humans.…”

mentioning

confidence: 96%

Identification of a Novel Glucosylsulfate Conjugate as a Metabolite of 3,4-Dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran-5,6-dione (ARQ 501, β-Lapachone) in Mammals

Savage¹,

Tyler²,

Miao³

et al. 2008

Drug Metab Dispos

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ARQ 501 (Fig. 1) is an investigational anticancer agent that consists of a fully synthetic small molecule (3,4-dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran-5,6-dione, ␤-lapachone, molecular mass 242 Da) in a stable HP␤CD formulation suitable for intravenous administration. In preclinical studies in vitro (Docampo et al., 1979; SchaffnerSabba et al., 1984;Chau et al., 1998;Li et al., 2000) and in vivo (Li et al., 1999;Ough et al., 2005), ARQ 501 showed activity against a variety of cancers. In a phase Ib clinical study, ARQ 501 showed promising anticancer activity against pancreatic cancer when administered in combination with gemcitabine. ARQ-501 is currently in several phase II cancer trials.Most pharmaceutical products (ϳ80%) that undergo biotransformation are cleared by the phase I cytochrome P450 enzymes (Coughtrie and Fisher, 2003). However, it is widely known that a second class of enzymes, the phase II enzymes, also plays a significant role in drug metabolism. Among the most common phase II enzymes are the UDPglucuronosyltransferases (UGTs), the sulfotransferases (SULTs), and the glutathione transferases (GSTs). Phase II metabolites are easily identified by mass spectrometry, as these biotransformation pathways are well characterized and the metabolites easily predicted by looking for mass differences when comparing the parent drug with its metabolite. For example, glucuronide, sulfate, and glutathione metabolites are easily predicted by an increase in mass of 176, 80, and 305 Da, respectively, to the mass of the parent drug (Kostiainen et al., 2003;Levsen et al., 2005). Over the last decade, highly sensitive and specific analytical techniques such as LC/MS/MS, high resolution quadrupole-time-of-flight (Q-Tof) mass spectrometry, and LC/NMR have been widely applied to the study of drug metabolism. Not surprisingly, this has led to the recent discovery of a number of novel metabolites (Jaggi et al., 2002;Miao et al., 2005;Chang et al., 2006;Endo et al., 2007) and, in some cases, to the discovery of novel metabolic pathways (Tang et al., 2003;Yin et al., 2003;Zhen et al., 2006). Although many studies have been conducted on ␤-lapachone (ARQ 501), there have been no previous reports on its metabolism either in animals or in humans. Preliminary metabolism studies for this compound were conducted with plasma from mice dosed intraperitoneally and rats dosed intravenously at 40 mg/kg with ARQ 501 formulated with HP␤CD. Later analyses were performed with human plasma samples obtained from a clinical study. In all species, the majority of conjugated product corresponds to glucuronidation or sulfation, but one metabolite representing a minor proportion of conjugate does not correspond to any commonly expected phase II metabolic process. The present study was conducted to characterize this rare metabolite, which has been identified as a novel glucosylsulfate conjugate. There are several accounts of a similar metabolic process occurring in cotton plants that were exposed to pesticides including profenofos (Capps et al.,...

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“…6A). In fact, the feasibility of this metabolomic approach was validated in a proof-of-concept experiment, in which the urine samples from a panel of human subjects of known CYP2D6 genotype, acquired from a previous study in our lab (Zhen et al, 2006), were analyzed by LC-MS and supervised MDA a . In debrisoquine-treated subjects, urine samples from poor metabolizers (PMs) were clearly separated from urine samples of extensive metabolizers (EMs) in the scores plot of an OPLS model (Fig.…”

Section: Metabolomic Approach For Identifying Human Xme Polymorphism mentioning

confidence: 99%

“…LC-MS measurement was conducted using UPLCQTOFMS (Waters), data processing using MarkerLynx™ (Waters), and MDA using SIMCA-P+ software (Umetrics). Data are adopted from a debrisoquine metabolism study (Zhen et al, 2006) …”

Section: Conclusion and Future Perspectivementioning

confidence: 99%

LC-MS-Based Metabolomics in Drug Metabolism

Chen

Gonzalez

Idle

2007

Drug Metabolism Reviews

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147

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Xenobiotic metabolism, a ubiquitous natural response to foreign compounds, elicits initiating signals for many pathophysiological events. Currently, most widely used techniques for identifying xenobiotic metabolites and metabolic pathways are empirical and largely based on in vitro incubation assays and in vivo radiotracing experiments. Recent work in our lab has shown that LC-MS-based metabolomic techniques are useful tools for xenobiotic metabolism research since multivariate data analysis in metabolomics can significantly rationalize the processes of xenobiotic metabolite identification and metabolic pathway analysis. In this review, the technological elements of LC-MSbased metabolomics for constructing high-quality datasets and conducting comprehensive data analysis are examined. Four novel approaches of using LC-MS-based metabolomic techniques in xenobiotic metabolism research are proposed and illustrated by case studies and proof-of-concept experiments, and the perspective on their application is further discussed.

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3,4-Dehydrodebrisoquine, a Novel Debrisoquine Metabolite Formed from 4-Hydroxydebrisoquine That Affects the CYP2D6 Metabolic Ratio

Cited by 15 publications

References 38 publications

Radiation Metabolomics. 2. Dose- and Time-Dependent Urinary Excretion of Deaminated Purines and Pyrimidines after Sublethal Gamma-Radiation Exposure in Mice

Radiation Metabolomics. 2. Dose- and Time-Dependent Urinary Excretion of Deaminated Purines and Pyrimidines after Sublethal Gamma-Radiation Exposure in Mice

Identification of a Novel Glucosylsulfate Conjugate as a Metabolite of 3,4-Dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran-5,6-dione (ARQ 501, β-Lapachone) in Mammals

LC-MS-Based Metabolomics in Drug Metabolism

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