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Expression of xenobiotic metabolising enzymes in lungs of horses with or without histological evidence of lower airway inflammation.

ABSTRACT: Mild, moderate and severe equine asthma is a problem for equine welfare. The aetiology of the disease is not known in detail but is likely multi-factorial. One important factor may be inhaled dust which carries harmful substances which may be bioactivated and thus can lead to local inflammation in the airways. The aim of this study was to investigate gene expression and protein localisation of cytochrome P450 (CYP) enzymes, superoxide dismutase and glutathione-S-transferases (GST) involved in bioactivation and detoxification of harmful substances in lungs of horses with or without histological evidence of lower airway inflammation. Significantly lower gene expression of CYP2A13 and GSTM1 was observed in lungs from horses with histological evidence of lower airway inflammation compared with horses without. A higher expression, although not significant, was found for CYP1A1 in horses with histological evidence of lower airway inflammation. There were no differences in gene expression of GSTP1 and SOD3. The proteins were localised in the respiratory epithelium which is of relevance as a defence to local exposure of inhaled harmful substances. In conclusion, our study reports differential gene expression of enzymes involved in bioactivation and detoxification of foreign substances in the lungs of horses with histological evidence of lower airway inflammation compared with horses without.

SUBMITTER: Lofgren M

PROVIDER: S-EPMC7840205 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Expression of xenobiotic metabolising enzymes in lungs of horses with or without histological evidence of lower airway inflammation.

Löfgren Maria M Larsson Pia P Lindberg Ronny R Hörnaeus Katarina K Tydén Eva E

Veterinary medicine and science 20200813 1

Mild, moderate and severe equine asthma is a problem for equine welfare. The aetiology of the disease is not known in detail but is likely multi-factorial. One important factor may be inhaled dust which carries harmful substances which may be bioactivated and thus can lead to local inflammation in the airways. The aim of this study was to investigate gene expression and protein localisation of cytochrome P450 (CYP) enzymes, superoxide dismutase and glutathione-S-transferases (GST) involved in bi ...[more]

PMID: 32791560

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Project description:This study aimed to document the effects of an eight hour journey on behavioural, clinical, haematological, environmental and respiratory parameters, and to identify possible associations between factors. Twelve horses underwent clinical examination, respiratory endoscopy with tracheal wash (TW) aspiration, and collection of venous and arterial blood before (BJ) and after the journey (AJ). TW were submitted for conventional quantitative bacteriological evaluation and genetic microbiome analyses. Behaviour was assessed in stables prior to transportation and throughout the journey. Transportation caused mild, but significant, effects on fluid and electrolyte balance and an acute phase response, characterized by neutrophilia, hyperfibrinogenaemia and hyperglobulinaemia. The proportion of neutrophils in TW, tracheal mucus and TW bacterial concentration was increased AJ, with preferential replication of Pasteurellaceae. Horse behaviour en route predicted clinical and respiratory outcomes. The frequency of stress related behaviours was greatest in the first hour of the journey, and balance-related behaviours were most common in the final hour of the journey. Horses which lowered their heads less frequently en route and showed more stress-related behaviours had higher physiological stress (serum cortisol and heart rate on arrival), increased tracheal mucus and inflammation scores, and higher TW bacterial concentration AJ (P<0.05). Six horses with abnormal lung auscultation AJ proved to have had higher tracheal inflammation scores at preloading (P = 0.017), an overall higher concentration of bacteria in their TW (P = 0.013), and an increased percentage of neutrophils in TW at five days AJ (P = 0.003) in comparison to the other horses. While transport-related health problems are multifactorial, clinical examination, including auscultation and endoscopic inspection of the lower respiratory tract before and after journey, and behavioural observation en route may identify animals at increased risk of transport associated respiratory disease.

Project description:RationaleCytochrome P450 enzymes are important in the metabolism of antidepressants. The highly polymorphic nature of these enzymes has been linked to variability in antidepressant metabolism rates, leading to hope regarding the use of P450 genotyping to guide treatment. However, evidence that P450 genotypic differences underlie the variation in treatment outcomes is inconclusive.ObjectivesWe explored the links between both P450 genotype and serum concentrations of antidepressant with antidepressant side effects, using data from the Genome-Based Therapeutic Drugs for Depression Project (GENDEP), which is a large (n = 868), pharmacogenetic study of depressed individuals treated with escitalopram or nortriptyline.MethodsPatients were genotyped for the enzymes CYP2C19 and CYP2D6, and serum concentrations of both antidepressant and primary metabolite were measured after 8 weeks of treatment. Side effects were assessed weekly. We investigated associations between P450 genotypes, serum concentrations of antidepressants and side effects, as well as the relationship between P450 genotype and study discontinuation.ResultsP450 genotype did not predict total side effect burden (nortriptyline: n = 251, p = 0.5638, β = -0.133, standard error (SE) = 0.229; escitalopram: n = 340, p = 0.9627, β = -0.004, SE = 0.085), study discontinuation (nortriptyline n = 284, hazard ratio (HR) = 1.300, p = 0.174; escitalopram n = 376, HR = 0.870, p = 0.118) or specific side effects. Serum concentrations of antidepressant were only related to a minority of the specific side effects measured: dry mouth, dizziness and diarrhoea.ConclusionsIn this sample where antidepressant dosage is titrated using clinical judgement, P450 genotypes do not explain differences between patients in side effects with antidepressants. Serum drug concentrations appear to only explain variability in the occurrence of a minority of specific side effects.

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Expression of xenobiotic metabolising enzymes in lungs of horses with or without histological evidence of lower airway inflammation.

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Expression of xenobiotic metabolising enzymes in lungs of horses with or without histological evidence of lower airway inflammation.

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