Nasal cavity enzymes involved in xenobiotic metabolism: effects on the toxicity of inhalants.

A decade ago, the ability of nasal tissues to metabolize inhalants was only dimly suspected. Since then, the metabolic capacities of nasal cavity tissues has been extensively investigated in mammals, including man. Aldehyde dehydrogenases, cytochrome P-450-dependent monooxygenases, rhodanese, glutathione transferases, epoxide hydrolases, flavin-containing monooxygenases, and carboxyl esterases have all been reported to occur in substantial amounts in the nasal cavity. The contributions of these enzyme activities to the induction of toxic effects from inhalants such as benzo-a-pyrene, acetaminophen, formaldehyde, cocaine, dimethylnitrosamine, ferrocene, and 3-trifluoromethylpyridine have been the subject of dozens of reports. In addition, the influence of these enzyme activities on olfaction and their contribution to vapor uptake is beginning to receive attention from the research community. Research in the next decade promises to provide answers to the many still unanswered questions posed by the presence of the substantial xenobiotic metabolizing capacity of the nasal cavity.     

Amino acid conjugation: contribution to the metabolism and toxicity of xenobiotic carboxylic acids

Despite being the first conjugation reaction demonstrated in humans, amino acid conjugation as a route of metabolism of xenobiotic carboxylic acids is not well characterised. This is principally due to the small number and limited structural diversity of xenobiotic substrates for amino acid conjugation. Unlike CYP and uridine 5'-diphosphate glucuronosyltransferase, which are localised in the endoplasmic reticulum, the enzymes of amino acid conjugation reside in mitochondria. Unique among drug metabolism pathways, amino acid conjugation involves initial formation of a xenobiotic acyl-CoA thioester that is then conjugated principally with glycine in humans. However, formation of the xenobiotic acyl-CoA thioester does not always infer subsequent amino acid conjugation. Evidence is presented that in the absence of glycine conjugation substrates that form acyl-CoA thioesters perturb mitochondrial function. This review discusses literature on the enzymes involved and the concept that xenobiotic substrate selectivity provides a barrier to protect the metabolic integrity of the mitochondria.     

Effect of some indole derivatives on xenobiotic metabolism and xenobiotic-induced toxicity in cultured rat liver slices.

In this study the effect of some indole derivatives on xenobiotic metabolizing enzymes and xenobiotic-induced toxicity has been examined in cultured precision-cut liver slices from male Sprague-Dawley rats. While treatment of rat liver slices for 72 hours with 2-200 microM of either indole-3-carbinol (I3C) or indole-3-acetonitrile (3-ICN) had little effect on cytochrome P-450 (CYP)-dependent enzyme activities, enzyme induction was observed after in vivo administration of I3C. The treatment of rat liver slices with 50 microM 3,3'-diindolylmethane (DIM; a dimer derived from I3C under acidic conditions) for 72 hours resulted in a marked induction of CYP-dependent enzyme activities. DIM appears to be a mixed inducer of CYP in rat liver slices having effects on CYP1A, CYP2B and CYP3A subfamily isoforms. Small increases in liver slice reduced glutathione levels and glutathione S-transferase activity were also observed after DIM treatment. While aflatoxin B1 and monocrotaline produced a concentration-dependent inhibition of protein synthesis in 72-hour-cultured rat liver slices, cytotoxicity was markedly reduced in liver slices cultured with 50 microM DIM. These results demonstrate that cultured rat liver slices may be employed to evaluate the effects of chemicals derived from cruciferous and other vegetables on CYP isoforms. In addition, liver slices can also be utilized to examine the ability of such chemicals to modulate xenobiotic-induced toxicity.     

Salt tolerance of rhizobial populations from contrasting environmental conditions: understanding the implications of climate change

Ecotoxicology - It is predicted that global climate change may alter environmental parameters such as rainfall distribution which in turn may alter the salinity of soils with unpredictable effects...     

Concurrent inflammation as a determinant of susceptibility to toxicity from xenobiotic agents.

Sensitivity to the toxic effects of xenobiotic agents is influenced by a number of factors. Recent evidence derived from studies using experimental animals suggests that inflammation is one of these factors. For example, induction of inflammation by coexposure to bacterial endotoxin, vitamin A or Corynebacterium parvum increases injury in response to a number of xenobiotic agents that target liver. These agents are diverse in chemical nature and in mechanism of hepatotoxic action. Factors critical to the augmentation of liver injury by inflammation include Kupffer cells, neutrophils, cytokines such as tumor necrosis factor-alpha (TNF-alpha) and lipid mediators such as prostaglandins, but these may vary depending on the xenobiotic agent and the mechanisms by which it alters hepatocellular homeostasis. In addition, the timing of inflammagen exposure can qualitatively alter the toxic response to chemicals. Inflammation-induced increases in susceptibility to toxicity are not limited to liver. Concurrent inflammation also sensitizes animals to the toxic effects of agents that damage the respiratory tract, kidney and lymphoid tissue. It is concluded that inflammation should be considered as a determinant of susceptibility to intoxication by xenobiotic exposure.     

Resveratrol modulates pyrogallol-induced changes in hepatic toxicity markers, xenobiotic metabolizing enzymes and oxidative stress

Previously, we reported that pyrogallol, an anti-psoriatic agent, causes hepatotoxicity in experimental animals and silymarin, an herbal antioxidant, reduces pyrogallol-induced changes [Upadhyay, G., Kumar, A., Singh, M.P., 2007. Effect of silymarin on pyrogallol- and rifampicin-induced hepatotoxicity in mouse. Eur. J. Pharmacol. 565, 190-201.]. The present study was undertaken to assess the effect of resveratrol against pyrogallol-induced changes in hepatic damage markers, xenobiotic metabolizing enzymes and oxidative stress. Swiss albino mice were treated intraperitoneally, daily with pyrogallol (40 mg/kg), for one to four weeks, along with respective controls. In some set of experiments, animals were pre-treated with resveratrol (10 mg/kg), 2 h prior to pyrogallol treatment, along with respective controls. Alanine aminotransaminase, aspartate aminotransaminase and bilirubin were measured in blood plasma and mRNA expression of cytochrome P-450 (CYP) 1A1, CYP1A2, CYP2E1, glutathione-S-transferase (GST)-ya and GST-yc, catalytic activity of CYP1A1, CYP1A2, CYP2E1, GST, glutathione reductase and glutathione peroxidase, lipid peroxidation and reduced glutathione (GSH) level were measured in liver. Resveratrol reduced pyrogallol-mediated increase in alanine aminotransaminase, aspartate aminotransaminase, bilirubin, lipid peroxidation and mRNA expression and catalytic activity of CYP2E1 and CYP1A2. Pyrogallol-mediated decrease in GST-ya and GST-yc expressions, GST, glutathione peroxidase and glutathione reductase activities and GSH content was significantly attenuated in resveratrol co-treated animals. CYP1A1 expression and catalytic activity were not altered significantly in any treated groups. The results demonstrate that resveratrol modulates pyrogallol-induced changes in hepatic toxicity markers, xenobiotic metabolizing enzymes and oxidative stress.     

Sites for xenobiotic activation and detoxication within the respiratory tract: implications for chemically induced toxicity

Results of in situ immunohistochemical investigations on several enzymes which participate in the bioactivation and detoxication of xenobiotics and of histochemical studies on aryl hydrocarbon hydroxylase activity summarized in this report clearly demonstrate that there are numerous sites within the respiratory tract at which xenobiotics can be bioactivated and detoxicated. The data presented, however, also reveal that xenobiotic-metabolizing enzymes and benzo[a]pyrene hydroxylase activity may not be distributed uniformly within individual segments (e.g., the nasal mucosa) of this organ system. Thus, it should be apparent from these findings that one cannot generalize as to how a given xenobiotic-metabolizing enzyme or xenobiotic monooxygenase activity normally is distributed either within or among the different segments of the respiratory tract. Additionally, since enzymes catalyzing the bioactivation and detoxication of xenobiotics usually are present within the same respiratory tract cells, it obviously is difficult to predict from these results which cell types within individual segments of this organ system most likely would be damaged as a consequence of exposure to xenobiotics which are biotransformed into cytotoxic metabolites by cytochrome(s) P-450. Although the cellular localizations and intercellular distributions of cytochromes P-450 BNF-B and MC-B parallel those of benzo[a]pyrene hydroxylase activity within the different segments of the respiratory tract in untreated rats, immunohistochemical findings on the inductions of these cytochrome P-450 isozymes are not entirely consistent with histochemical observations on the enhancement of benzo[a]pyrene hydroxylase activity by Aroclor 1254 within the nasal mucosa and by both Aroclor 1254 and 3-methylcholanthrene within the lung. It must be appreciated, however, that other cytochrome P-450 isozymes undoubtedly are present and inducible in the nasal mucosa and lung and, further, that these hemeproteins, although being immunochemically unrelated to the cytochrome P-450 isozymes studied, also could catalyze aryl hydrocarbon hydroxylase activity. Nevertheless, these immunohistochemical and histochemical findings do demonstrate that one cannot generalize as to how chemicals which induce the same xenobiotic-metabolizing enzyme will affect that enzyme within different segments of the respiratory tract and, moreover, that inducers of cytochromes P-450 can alter differentially the extents to which different cells within a given segment of the respiratory tract (e.g., the nasal mucosa) participate in the oxidative metabolism of xenobiotics.     

气候变化对传染病影响的研究进展

全球气候变化是当今世界十大环境问题之首,其变化趋势是全球变暖和极端天气增多。气候是影响传染病传播的重要因素之一,从病原体及其携带者、传播途径和人体自身抵抗力等方面直接或间接影响传染病的发病趋势。改善的全球气候,监测气候变化和传染病发生动向,可以提供制定传染病防治策略的依据,从而能够及时采取有效的防控措施,减少国家和人民的损失。     

Use of precision-cut rat liver slices for studies of xenobiotic metabolism and toxicity: comparison of the Krumdieck and Brendel tissue slicers

1. In this study we have compared freshly cut and cultured precision-cut rat liver slices produced by the Krumdieck and Brendel-Vitron tissue slicers. 2. No significant differences were observed in levels of protein, potassium, total glutathione (i.e. GSH and GSSG), reduced glutathione (GSH) and cytochrome P450 and activities of 7-ethoxyresorufin O-deethylase and 7-benzoxyresorufin O-debenzylase in freshly cut rat liver slices produced by the two tissue slicers. However, levels of oxidized glutathione (GSSG) were significantly greater in liver slices produced with the BrendelVitron tissue slicer. 3. Precision-cut rat liver slices produced with both tissue slicers were cultured for 0 (i.e. a 1-h preincubation), 24 and 72 h in a dynamic organ culture system in an atmosphere of either 95% O₂/5% CO₂ or 95% air/5% CO₂. 4. Apart from small differences in glutathione levels in 0 and 24 h cultured liver slices, no significant differences were observed in the parameters measured between liver slices prepared with both tissue slicers and cultured in both gas phases. 5. With liver slices produced by both tissue slicers 50 μM sodium arsenite produced a greater induction of heat shock protein 70 levels in slices cultured for 24 h in a high oxygen than in an air atmosphere. 6. These results suggest that both tissue slicers can readily produce precision-cut liver slices for studies of xenobiotic metabolism and toxicity. However, the data suggest that for any given application of precision-cut tissue slicesit is desirable to establish optimal culture conditions.     

Environmental influences on human foetal and placental xenobiotic metabolism

Summary The human foetus is more capable of metabolizing xenobiotics than foetuses of common laboratory animal species. However, xenobiotic metabolism in animal foetuses is inducible by the exposure of the mother to various inducers during late pregnancy. Xenobiotic metabolism in neonates is more easily inducible than in foetal animals. With respect to the human foetus at mid-pregnancy, the hepatic enzyme systems do not seem to be readily inducible by exogenous inducers, whereas the placental monooxygenase system is almost totally dependent on maternal cigarette smoking. In the human newborn, indirect evidence points to the possibility of induction by potential inducers. The ontogenetic development of xenobiotic metabolism is probably regulated by endogenous hormones. It is possible that environmental factors may affect these normal regulatory and imprinting phenomena and thus lead to permanent disturbances in xenobiotic metabolism.Presented at the International Workshop on Perinatal and Pediatric Aspects of Clinical Pharmacology, Heidelberg, Federal Republic of Germany, 27–29 February 1980     

Effect of 1,4-dibromobenzene and 1,2,4-tribromobenzene on xenobiotic metabolism

1,4-Dibromobenzene and 1,2,4-tribromobenzene were administered po to male rats for 45 and 90 days, with or without a 30-day recovery period. After 45 or 90 days of administration, both 1,4-dibromobenzene (10 and 20 mg/kg) and 1,2,4-tribromobenzene (2.5, 5, and 10 mg/kg) increased liver to body weight ratios, cytochrome P-450 content, EPN detoxification, and azoreductase activity. In addition, 1,2,4-tribromobenzene, which was the more potent inducer, increased NADPH-cytochrome c reductase activity and benzpyrene hydroxylase activity. Glucuronyltransferase activity was not increased by either compound. These effects were not found following the 30-day recovery period. It is concluded that both of these simple brominated benzenes can induce the metabolism of xenobiotics but that the effects are not prolonged following the cessation of administration of the compounds.     

Impacts of salicylic acid in Mytilus galloprovincialis exposed to warming conditions

While many studies have been conducted on drug-inducing alterations in the aquatic environment, little is known about their interaction with climate change, such as rising temperatures. To increase knowledge on this topic, Mytilus galloprovincialis mussels were exposed to two different temperatures 17 ± 1 °C (control) and 21 ± 1 °C in the absence and presence of salicylic acid (SA) (4 mg/L) for 28 days. Salicylic acid in the water and tissues was measured and its impact reported through biomarker responses including: energy metabolism (electron transport system (ETS) activity, glycogen (GLY), protein (PROT) and lipids (LIP) contents), oxidative stress markers (activity of the enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx)), glutathione balance between the reduced and the oxidized forms (GSH/GSSG), and damage to membrane lipids (lipid peroxidation - LPO). The mussels responded differently if the stresses imposed were single or combined, with greater impacts when both stressors were acting together. Contaminated mussels exposed to high temperatures were unable to increase their metabolic capacity to restore their defence mechanisms, reducing the expenditure of LIP. In the presence of SA and increased temperature antioxidant defences respond differently, with higher SOD levels and inhibition of CAT. The present study highlights not only the negative impact of warming and SA, but especially how temperature increase will promote the impact of SA in M. galloprovincialis, which under predicted climate change scenarios may greatly impair population maintenance and ecosystem biodiversity.