Applications of accelerator mass spectrometry for pharmacological and toxicological research

Brown, Karen; Tompkins, Elaine M.; White, Ian N.H.

doi:10.1002/mas.20059

Cited by 61 publications

(66 citation statements)

References 95 publications

(109 reference statements)

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“…Only one recent study reported mass spectrometric identification and structural confirmation of an adduct between PhIP and a model albumin peptide encompassing the reactive Cys34 residue (Chepanoske et al, 2004). Due to the very low environmentally relevant doses of these heterocyclic amines, sensitivity in animal and human studies is often a limiting factor: therefore a sophisticated attomole-sensitivity technique, accelerator mass spectrometry (Brown, Tompkins, & White, 2006) has been employed to measure DNA-and protein-heterocyclic amine adducts (Dingley et al, 1998;Turteltaub et al, 1999).…”

Section: Food Lifestyle and Indoor Air Carcinogensmentioning

confidence: 97%

Toward an “omic” physiopathology of reactive chemicals: Thirty years of mass spectrometric study of the protein adducts with endogenous and xenobiotic compounds

Rubino

Pitton

Fabio

et al. 2009

Mass Spectrometry Reviews

109

170

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Cancer and degenerative diseases are major causes of morbidity and death, derived from the permanent modification of key biopolymers such as DNA and regulatory proteins by usually smaller, reactive molecules, present in the environment or generated from endogenous and xenobiotic components by the body's own biochemical mechanisms (molecular adducts). In particular, protein adducts with organic electrophiles have been studied for more than 30 [see, e.g., Calleman et al., 1978] years essentially for three purposes: (a) as passive monitors of the mean level of individual exposure to specific chemicals, either endogenously present in the human body or to which the subject is exposed through food or environmental contamination; (b) as quantitative indicators of the mean extent of the individual metabolic processing which converts a non-reactive chemical substance into its toxic products able to damage DNA (en route to cancer induction through genotoxic mechanisms) or key proteins (as in the case of several drugs, pesticides or otherwise biologically active substances); (c) to relate the extent of protein modification to that of biological function impairment (such as enzyme inhibition) finally causing the specific health damage. This review describes the role that contemporary mass spectrometry-based approaches employed in the qualitative and quantitative study of protein-electrophile adducts play in the discovery of the (bio)chemical mechanisms of toxic substances and highlights the future directions of research in this field. A particular emphasis is given to the measurement of often high levels of the protein adducts of several industrial and environmental pollutants in unexposed human populations, a phenomenon which highlights the possibility that a number of small organic molecules are generated in the human organism through minor metabolic processes, the imbalance of which may be the cause of "spontaneous" cases of cancer and of other degenerative diseases of still uncharacterized etiology. With all this in mind, it is foreseen that a holistic description of cellular functions will take advantage of new analytical methods based on time-integrated metabolomic measurements of a new biological compartment, the "adductome," aimed at better understanding integrated organism response to environmental and endogenous stressors.

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Section: Food Lifestyle and Indoor Air Carcinogensmentioning

confidence: 97%

Toward an “omic” physiopathology of reactive chemicals: Thirty years of mass spectrometric study of the protein adducts with endogenous and xenobiotic compounds

Rubino

Pitton

Fabio

et al. 2009

Mass Spectrometry Reviews

109

170

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“…14 C]-labelled resveratrol and accelerator mass spectrometry [35] to elucidate the full plasma pharmacokinetic profile of a dietary attainable dose of resveratrol in healthy volunteers as well as measuring prostate and colorectal tissue concentrations in patients undergoing surgery.…”

Section: High Dose Versus Dietary Dosementioning

confidence: 99%

Resveratrol in human cancer chemoprevention – Choosing the ‘right’ dose

Scott

Steward

Gescher

et al. 2011

Molecular Nutrition Food Res

Self Cite

108

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There is now robust preclinical evidence to suggest that resveratrol possesses cancer chemopreventive properties. A series of clinical pilot studies has provided insights into its pharmacokinetics, and data on its human antineoplastic pharmacodynamics start to emerge. It is likely that resveratrol will be developed further in the clinic as a putative cancer chemopreventive agent. The question that remains unresolved is: What is the most suitable dose of resveratrol for effective cancer preventive intervention? Mechanistic studies in cells in vitro have almost invariably used concentrations of resveratrol in the 10(-5) to 10(-4) M range, which is much higher than those which can be achieved in the human biophase after consumption of doses up to 1 g. Many of the preclinical efficacy studies in rodent models of carcinogenesis have employed doses which are dramatically above those which can be ingested with the diet. New experimental paradigms need to be used to obtain information on pharmacological changes elicited by resveratrol when present at very low concentrations or when administered at dietary-relevant doses.

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“…Advances in HPLC technology (e.g., ultra high performance liquid chromatography or UHPLC) also have contributed to the greatly enhanced capabilities of contemporary LC-MS/MS systems, not only in terms of chromatographic resolution and associated speed of separations, but also with regard to the capacity and robustness afforded by the current generation of columns, autosamplers, pumping systems, and so forth. Accelerator mass spectrometry (AMS), a technique employed originally for applications in the geophysical sciences, has been developed as an exquisitely sensitive tool for biomedical applications, including studies of drug disposition, in which trace amounts of a radioisotope (e.g., 14 C) can be detected and quantified in blood or excreta following the administration of a microdose of the agent of interest (30). In the area of therapeutic proteins and monoclonal antibodies, matrix-assisted laser desorption-ionization (MALDI) mass spectrometry has become an important technique (in addition to ESI) not only for qualitative applications but also as a reference method against which immunological assays (e.g., ELISA) can be validated for determining the PK properties of these biologics in animals and humans (31).…”

Section: The Past 20 Yearsmentioning

confidence: 99%

Metabolism and Toxicity of Drugs. Two Decades of Progress in Industrial Drug Metabolism

Baillie

2007

Chem. Res. Toxicol.

188

116

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The science of drug metabolism and pharmacokinetics (DMPK) has developed significantly over the past 20 years, and its functional role in today's pharmaceutical industry has matured to the point where DMPK has become an indispensable discipline in support of drug discovery and development. While contributions to the lead optimization phase of discovery efforts have been particularly noteworthy in helping to select only the best drug candidates for entry into development, it should be recognized that the scope of DMPK spans the continuum of discovery through clinical evaluation and even into the post-marketing phase; as such, the breadth of DMPK's involvement is almost unique in contemporary pharmaceutical research. This perspective summarizes notable advances in the field, many of which have been made possible by technological developments in areas such as molecular biology, genetics, and bioanalytical chemistry, and highlights the critical nature of key partnerships between Drug Metabolism, Medicinal Chemistry, and Safety Assessment groups in attempting to advance drug candidates with a low potential for causing adverse events in humans. Finally, some speculative predictions are made of the future role of DMPK in pharmaceutical research, where current advances in our mechanistic understanding of the molecular processes that control the absorption, disposition, metabolism, elimination, and toxicity of drugs and their biotransformation products will combine to further enhance the impact of DMPK in drug discovery and development.

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Applications of accelerator mass spectrometry for pharmacological and toxicological research

Cited by 61 publications

References 95 publications

Toward an “omic” physiopathology of reactive chemicals: Thirty years of mass spectrometric study of the protein adducts with endogenous and xenobiotic compounds

Toward an “omic” physiopathology of reactive chemicals: Thirty years of mass spectrometric study of the protein adducts with endogenous and xenobiotic compounds

Resveratrol in human cancer chemoprevention – Choosing the ‘right’ dose

Metabolism and Toxicity of Drugs. Two Decades of Progress in Industrial Drug Metabolism

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