An Effective Assessment of Simvastatin-Induced Toxicity with NMR-Based Metabonomics Approach

BACKGROUND: Simvastatin, which is used to control elevated cholesterol levels, is one of the most widely prescribed drugs. However, a daily excessive dose can induce drug-toxicity, especially in muscle and liver. Current markers for toxicity reflect mostly the late stages of tissue damage; thus, more efficient methods of toxicity evaluation are desired. METHODOLOGY/PRINCIPAL FINDINGS: As a new way to evaluate toxicity, we performed NMR-based metabonomics analysis of urine samples. Compared to conventional markers, such as AST, ALT, and CK, the urine metabolic profile provided clearer distinction between the pre- and post-treatment groups treated with toxic levels of simvastatin. Through multivariate statistical analysis, we identified marker metabolites associated with the toxicity. Importantly, we observed that the treatment group could be further categorized into two subgroups based on the NMR profiles: weak toxicity (WT) and high toxicity (HT). The distinction between these two groups was confirmed by the enzyme values and histopathological exams. Time-dependent studies showed that the toxicity at 10 days could be reliably predicted from the metabolic profiles at 6 days. CONCLUSIONS/SIGNIFICANCE: This metabonomics approach may provide a non-invasive and effective way to evaluate the simvastatin-induced toxicity in a manner that can complement current measures. The approach is expected to find broader application in other drug-induced toxicity assessments

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Circadian and cyclic environmental determinants of blood pressure patterning and implications for therapeutic interventions

Blood pressure (BP) exhibits significant 24 h variation; in most normotensive and uncomplicated hypertensive persons, BP declines during the first half of nighttime sleep by 10–20% from its daytime mean level, starts rising in the second half of sleep, further increases with commencement of diurnal activity, and peaks in the afternoon or early evening. Environmental 24 h cycles of temperature and noise; behavior-driven nyctohemeral patterning of food, liquid, and stimulant consumption, posture, mental and emotional stress, and physical activity; plus innate circadian rhythms in wake/sleep, autonomic nervous, hypothalamic-pituitary-adrenal, renal hemodynamic, opioid, renin-angiotensin-aldosterone, endothelial, and vasoactive peptide systems constitute the key determinants of the BP day/night variation. The current perspective is the environmental and behavioral cycles are far more influential than the innate circadian ones in determining the BP nyctohemeral profile. Yet, the facts that the: (i) BP 24h pattern of secondary hypertension, e.g., diabetes and other endocrine disorders, renal disease, heart failure, is different -- BP fails to decline as expected during nighttime sleep typically due to pathological alteration of autonomic nervous system and other influential circadian rhythms, and (ii) scheduling of conventional long-acting medications at bedtime, rather than in the morning, results in much better hypertension control and vascular risk reduction, presumably because highest drug concentration coincides closely with the peak of most key circadian determinants of the BP 24h profile, indicates the endogenous rhythmic influences are of much greater importance than previously appreciate

Oxidative stress and vascular damage in hypertension

Metabolism of oxygen by cells generates potentially deleterious reactive oxygen species, including superoxide anion radical, hydrogen peroxide, and hydroxyl radical. Under normal physiologic conditions the rate and magnitude o oxidant formation is balanced by the rate of oxidant elimination. However, an imbalance between prooxidants and antioxidants results in oxidative stress, which is the pathogenic outcome of the overproduction of oxidants that overwhelms the cellular antioxidant capacity. There is increasing evidence that an elevation of oxidative stress and associated oxidative damages are mediators of vascular injury in various cardiovascular pathologies, including hypertension, atherosclerosis, and ischemia-reperfusion. This review focuses on the vascular effects of reactive oxygen species and the role of oxidative stress in vascular damage in hypertension