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.
a b s t r a c tSecondary metabolites (SMs) are organic compounds of low molecular mass that represent a vast chemical diversity. In plants, one of their preeminent roles is their repellent activity against predators. The Eurasian red squirrels (Sciurus vulgaris) is one of the most important predators of conifer tree seeds in boreal and alpine forests in Europe. Its population dynamics and space use are strongly affected by the size of Norway spruce (Picea abies) seed-crops, but not by silver fir (Abies alba) seed-crops. Moreover, squirrel heavily feed on spruce seeds but tend to avoid fir seeds, although the latter has a higher seed-energy content per cone. We tested the hypothesis that a higher concentration of some SMs in fir than in spruce seeds and/or cone scales, the protective tissue of seeds, was related with squirrel feeding preferences. We determined terpene concentrations in the cyclohexane extract of seeds and scales by gas-chromatography-electron ionisation mass-spectrometry (GC/EI-MS), and measured the protein precipitation activity of tannin contained in spruce and fir seeds and scales. Of the nearly 300 separated chemical entities, only limonene, ␣-and -pinene and myrcene occurred in all samples and their levels accounted for 80% or more of all cyclohexane-extractable materials of fir and for less than 50% of that of spruce. In fir, limonene was by far the most abundant compound, and fir scales had a 13 times higher concentration of ␣-pinene than spruce scales. Fir seeds had much higher limonene concentrations than fir scales and than seeds or scales of spruce. Tannin concentrations were higher in cone scales than in seeds, with no differences between the two tree species. This study suggests that high concentrations of limonene might reduce the feeding activity of red squirrels on fir seeds, and that the preferred spruce seeds had much lower monoterpene concentrations. Feeding trials using food items treated with different concentrations of limonene will be carried out to confirm this hypothesis.
S-methylcysteine (SMC) is a minor amino acid naturally excreted in human urine, a protective agent against oxidative stress and a biotransformation product of the fumigant biocide methyl bromide and of nicotine. A metabolic source of SMC is catabolism of the repair catalytic protein MGMT (EC 2.1.1.37), which specifically removes the methyl group from the modified DNA nucleotide O-6-methyl-guanine to revert the normal GC base pairing. To assess the value of SMC and of S-methylmercapturic acid (SMMA) as candidate biomarkers of proliferative phenomena, a sensitive analytical method by GC-MS was applied in a pilot study of healthy subjects to assess their urinary elimination and the intra- and inter-individual variability. Extractive alkylation with butylchloroformate-n-butanol-pyridine (Husek technique) was employed for sample derivatization and isotope dilution GC-MS with S-[CD(3) ]-SMC and -SMMA was applied for specific and sensitive detection. To resolve the target analytes from the main coeluting interferents in the derivatized urine extract a medium-polarity stationary phase was employed. SMMA was not detected in the morning urine of three healthy fertile-age women followed for one month above the minimum detectable level of approx. 500 µg/L while SMC concentrations were in the 0.02-0.7 µg/mL range (n = 61) with large inter-day and inter-individual variations. In a young healthy male urine samples taken throughout a few days yielded concentrations in the same 90-810 µg/L range (n = 11). These preliminary results points at SMC as a candidate biomarker for the study of methylation turnover in several biochemical processes.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.