Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015672 (fatigue)
 51,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of decreased hepatic energy state on xenobiotic conjugation was examined in vivo. The pharmacokinetics of acetaminophen, a drug that is conjugated with glucuronic acid, sulfate and glutathione, was analyzed in rats when the hepatic energy state had been decreased by ethionine or fructose. Treatment with ethionine or fructose reduced the hepatic adenosine triphosphate/diphosphate ratio by 30 to 65% and 43 to 54% and the phosphorylation potential by 50 to 80 and 43%, respectively. Ethionine treatment increased uridine triphosphate (UTP) and other UTP-derived nucleotides. However, uridine diphosphoglucuronic acid levels were decreased by 44% whereas uridine diphosphoglucose concentration was increased by 20%. This effect may be due to a decrease in redox state. Fructose treatment reduced the concentrations of UTP and UTP-derived nucleotides. Uridine diphosphoglucose was reduced by 50% and uridine diphosphoglucuronic acid by about 40%. Ethionine and fructose also decreased glutathione and adenosine 3'-phosphate 5'-phosphosulfate concentrations in the liver by 30 to 50%. During the period of decreased energy state, biliary and urinary excretion of acetaminophen (2 mmol/kg i.v.) and its metabolites was reduced 57% by ethionine and 66% by fructose. This was caused by decreased synthesis and excretion of the conjugates. Synthesis of the conjugates was impaired because of decreased hepatic cosubstrate levels. The present data suggest that energy state must be severely compromised before decreases in conjugation are observed in vivo. Thus, it is unlikely that energy state is often a limitation in the conjugation and excretion of xenobiotics.
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PMID:Effect of reduced hepatic energy state on acetaminophen conjugation in rats. 373 28

Major advances have been made in understanding the relatively novel group of vasoactive (vasodilatory) neuropeptides (VNs) in humans. VNs comprise a novel but expanding group of substances having immunoregulation, inflammation modulation, neurotransmitter, neurotrophic, hormonal and metabolic functions. These substances may control gene expression for mRNA for themselves and their receptors. They have complex relationships with gaseous and other neurotransmitters and xenobiotic substances. Theoretical arguments have implicated these substances in autoimmune phenomena resulting in fatigue-related conditions such as chronic fatigue syndrome (CFS), sudden infant death syndrome (SIDS), fibromyalgia (FM) and Gulf War syndrome (GWS) but remain unproven. As well as possibly spontaneous onset, the precipitating causes of VN autoimmune dysfunction are likely to be a combination of genetic predisposition, infection and xenobiotic substances. Therapeutic and preventive possibilities for postulated VN autoimmune conditions will be influenced by the complex patholophysiology underpinning them. Some speculative possibilities are VN substitution/replacement, preservation of biological effect, epigenetic DNA modifications, plasma exchange, anti-cholinesterases, e.g., pyridostigmine, corticosteroids and other drug treatments, thymectomy, intravenous immunoglobulin and anti-idiotype antibodies, and CpG/DNA vaccines. Prevention and treatment of possible VN autoimmune fatigue-related disorders may prove to be important areas for future research and development.
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PMID:Therapeutic and preventive interventions for postulated vasoactive neuropeptide autoimmune fatigue-related disorders. 1604 95

Chemical defensive system consisting of bio-sensoring, transmitting, and responsive elements has been evolved to protect multi-cellular organisms against environmental chemical insults (xenobiotics) and to maintain homeostasis of endogenous low molecular weight metabolites (endobiotics). Both genetic and epigenetic defects of the system in association with carcinogenesis and individual sensitivity to anti-tumor therapies have been intensely studied. Recently, several non-tumor human pathologies with evident environmental components such as rather rare functional syndromes (multiple chemical sensitivity, chronic fatigue, Persian Gulf, and fibromyalgia now collectively labeled as idiopathic environmental intolerances) and common diseases (vitiligo and systemic lupus erythematosus) have become subjects of the research on the impaired metabolism and detoxification of xenobiotics and endogenous toxins. Here, we collected and critically reviewed epidemiological, genetic, and biochemical data on the involvement and possible role of cytochrome P450 super family enzymes, glutathione-S-transferase isozymes, catechol-O-methyl-transferase, UDP-glucuronosyl transferases, and proteins detoxifying inorganic and organic peroxides (catalase, glutathione peroxidase, and peroxiredoxin) in the above pathologies. Genetic predisposition assessed mainly by single nucleotide polymorphism and gene expression analyses revealed correlations between defects in genes encoding xenobiotic-metabolizing and/or detoxifying enzymes and risk/severity of these syndromes/diseases. Proteome analysis identified abnormal expression of the enzymes. Their functions were affected epigenetically leading to metabolic impairment and, as a consequence, to the negative health outcomes shared by some of these pathologies. Data obtained so far suggest that distinct components of the chemical defensive system could be suitable molecular targets for future pathogenic therapies.
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PMID:The chemical defensive system in the pathobiology of idiopathic environment-associated diseases. 2020 26

Primary biliary cholangitis (PBC) is an autoimmune chronic cholestatic liver disease characterized by biliary destruction and progressive intrahepatic cholestasis. PBC primarily affects women in their fifth or sixth decade of life. Although many patients are asymptomatic at presentation, fatigue, pruritus, sicca syndrome, and upper abdominal discomfort are common symptom manifestations. The etiology of PBC is thought to be related to interactions between underlying genetic predisposition and microbial and xenobiotic environmental triggers. The diagnosis is established in the setting of biochemical cholestasis and antimitochondrial or disease-specific antinuclear antibodies, with histologic evidence of nonsuppurative granulomatous cholangitis being supportive, but not required, to confirm disease. Care of patients with PBC encompasses therapies to slow disease progression, manage symptoms associated with cholestasis, and treat complications of advanced liver disease. Risk stratification based on simple clinical and laboratory parameters, either as binary response criteria and/or continuous models, helps identify the patients at greatest risk of poor outcome. First-line therapy to slow disease progression is ursodeoxycholic acid (UDCA), which is the mainstay of pharmacologic therapy for all patients with PBC. The only currently approved second-line option for patients who do not achieve adequate biochemical response or are intolerant to UDCA is the novel farnesoid X receptor agonist obeticholic acid. Off-label use of peroxisome proliferator-activated receptor agonists, including the fibrate class of drugs where available, is also recognized as an option for patients.
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PMID:A Practical Review of Primary Biliary Cholangitis for the Gastroenterologist. 3106 56

Chronic fatigue, in its various manifestations, frequently co-occur with pain, sleep disturbances and depression and is a non-communicable condition which is rapidly becoming endemic worldwide. However, it is handicapped by a lack of objective definitions and diagnostic measures. This has prompted the World Health Organization to develop an international instrument whose intended purpose is to improve quality of life (QOL), with energy and fatigue as one domain of focus. To complement this objective, the interface between detoxification, the exposome, and xenobiotic-sensing by nuclear receptors that mediate induction of biotransformation-linked genes, is stimulating renewed attention to a rational development of strategies to identify the metabolic profiles in complex multifactorial conditions like fatigue. Here we present results from a seven-year study of a cohort of 576 female patients suffering from low to high levels of chronic fatigue, in which phase I and phase II biotransformation was assessed. The biotransformation profiles used were based on hepatic detoxification challenge tests through oral caffeine, acetaminophen and acetylsalicylic acid ingestion coupled with oxidative stress analyses. The interventions indicated normal phase I but increased phase II glucuronidation and glycination conjugation. Complementarity was indicated between a fatigue scale, medical symptoms and associated energy-related parameters by application of Chi-square Automatic Interaction Detector (CHAID) analysis. The presented study provides a cluster of data from which we propose that multidisciplinary inputs from the combination of a fatigue scale, medical symptoms and biotransformation profiles provide the rationale for the development of a comprehensive laboratory instrument for improved diagnostics and personalized interventions in patients with chronic fatigue with a view to improving their QOL.
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PMID:Biotransformation profiles from a cohort of chronic fatigue women in response to a hepatic detoxification challenge. 3107 16