Induction of hepatic drug metabolizing enzymes in mammals by pesticides: A review

Abstract

The induction of drug metabolizing enzymes in mammals is summarized including both enzymes of the cytochrome P‐450‐dependent microsomal mixed function oxidase system and glutathione S‐transferases. Particular emphasis is placed on the role of pesticides as inducers, the early work being summarized while investigations carried out at North Carolina State University are considered in greater detail. Finally, the possible significance of induction is considered.     

Effect of chronic exposure to cadmium on hepatic drug metabolism

In an attempt to examine the chronic effect of low levels of cadmium on hepatic drug-metabolizing enzyme system, an experiment was carried out in which growing male rats were given 0, 5, 10, and 20 ppm of cadmium in drinking water for a period of 8 weeks. An ip administration of a hypnotic dose of pentobarbital to the cadmium-treated and the control rats 24 hr following the termination of the experiment exhibited that there was no significant difference in the drug metabolism in control and any of the treated groups. Next, liver microsomes were isolated from animals in all groups to study their ability to metabolize drugs in vitro. The results indicated that the activity of benzphetamine N-demethylase and aniline hydroxylase, and the concentration of microsomal cytochrome P-450 were almost identical in the control and treated groups. On the other hand, a single ip dose of cadmium (2 mg/kg) caused significant decrease in the vivo and in vitro microsomal drug metabolism. These results suggest that although a single ip dose of cadmium (2 mg/kg) causes significant inhibition of drug metabolism, chronic exposure to cadmium up to 20 ppm in drinking water over a period of 8 weeks is unlikely to affect hepatic drug metabolism.     

二噁英降解酶的研究进展

二噁英是一类广泛分布于环境中的持久性有机污染物,它们能够在食物链中逐级积累,并可引发多种细胞毒性,严重影响生态系统和人类健康。在众多二噁英降解方法中,生物降解法以环境友好和低成本等优点一直受到国内外学者的青睐,而二噁英降解酶是生物降解法中的关键物质。简要综述了近年来二噁英典型降解酶的降解机制、效果和编码基因等方面研究进展,并对二噁英降解酶未来的研究和应用方向进行了展望。     

An evaluation of the cytochrome P450 inhibition potential of selected pesticides in human hepatic microsomes

The goal of this work was to study the ability of 18 pesticides to inhibit selective model activities for all major xenobiotic-metabolizing enzymes, namely CYP1A1/2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4. Generally organophosphorus insecticides were the most potent and extensive inhibitors, especially towards CYP1A1/2 (IC₅₀ values of chlorpyrifos, fenitrothion and profenofos ～3 μ M), CYP2B6 (IC₅₀ values of chlorpyrifos and fenitrothion 2.5 μ M), CYP2C8 (fenitrothion 4.3 μ M), CYP2C9 (fenitrothion and malathion 4.8 and 2.5 μ M, respectively), CYP2D6 (chlorpyrifos and phenthoate ～ 3 μ M) and CYP3A4 (chlorpyrifos, fenitrothion and phenthoate 3–4 μ M). Otherwise there were quite considerable differences in potency and extent of inhibition between different organophosphates. Pyrethroids were in general very weak or inactive. Deltamethrin and fenvalerate were potent inhibitors of CYP2D6 (IC₅₀ values of ～ 3 μ M) while lambda-cyhalothrin potently inhibited both CYP2D6 and CYP3A4-mediated activities (IC₅₀'s about 3–4 μ M). Some pesticides caused relatively potent inhibitions sporadically (carbendazim, CYP2D6, IC₅₀ = 12 μ M; atrazine, CYP3A4, IC₅₀ = 2.8 μ M; glyphosate, CYP2C9, IC₅₀ = 3.7 μ M; hexaflumuron, IC₅₀ = 6.0 μ M). With the exceptions of alpha-cypermethrin, cypermethrin, isoproturon, carbaryl and abamectin, most pesticides inhibited relatively potently at least one CYP-selective activity, which may have relevance for potential interactions in occupational exposures and for further studies on the CYP-associated metabolism of respective pesticides.     

Effects of cadmium,zinc, copper and manganese on hepatic parenchymal cell gluconeogenesis

Abstract

The effects of divalent cations on gluconeogenesis in enzy‐matically isolated rat hepatic parenchymal cells were examined. Cadmium, zinc and copper decreased glucose production from lactate (10 mM). However, manganese at 0.05 to 1.0 mM levels stimulated gluconeogenesis by the cells and reduced the effects of the Cd⁺², Zn⁺² and Cu⁺² on gluconeogenesis. The results indicate that under these in vitro conditions the cations altered an aspect of hepatic function—gluconeogenesis from lactate.     

Safening activity of natural hydroxamic acids and analogous compounds against herbicide injury to maize

Abstract

Safening activities of natural compounds DIMBOA, DIBOA, and MBOA, as well as synthetic 1,4‐benzoxazin‐3‐ones were tested against acetochlor and EPTC injuries to maize. No safening activities of natural products and from low to moderate activity of synthetic benzoxazinones were observed. In order to explain inefficacy of natural compounds we studied the influence of these molecules on enzymes participating in metabolic detoxication of acetochlor and EPTC. Pretreatment with DIMBOA elevated maize cytochrome P450 levels. Pretreatments with chemicals containing 1,4‐benzoxazin‐3‐one backbone did not alter glutathione S‐transferase enzyme activities. However, all natural products inhibited glutathione S‐transferase activity of roots and shoots in vitro after addition to the enzyme. Safening ineffectiveness of natural hydroxamic acids may be explained by their inhibitory effects on GST enzymes due to their reaction with sulfhydryl groups on the enzyme.     

Reproductive impairment of sea urchin upon chronic exposure to cadmium. Part II: Effects on sperm development

Chronic pollution may impair the reproductive success of adult organisms through a decrease in the quality of gametes. Our parallel study on gamete quality, showed that male sea urchins were more sensitive than the females towards cadmium pollution. The effects of chronic exposure to 0.01 and 1 ppm Cd2+ on sperm development of the sea urchin Anthocidaris crassispina were studied. Despite the fact that no significant change in gonad index was observed when sea urchins were exposed to both levels of Cd2+ for 4 weeks, deposition of electron-dense materials was conspicuous at the wall and intracellular space of male gonads. Apparent cytological alterations were observed in sperm cells, including changes in morphology of nuage in spermatogonia. The discrete, granular bodies of nuage were replaced by a large electron-dense body. Spermatozoa with short, incomplete 'broken' tails (scanning electron microscope observation) or tails of spermatids/spermatozoa with extraordinary electron-density (transmission electron microscope observation) were more abundant in gonads exposed to both levels of Cd2+. Mitochondrial cristae deformation was observed for sperm cells at all stages of development. Sperm plasma membrane also became more convoluted but acrosome remained intact. The observed cytological distortion of sperm tails and mitochondria/midpiece could help to explain the decline in motility as well as poor perseverance in sperm produced by sea urchins exposed to cadmium observed in our earlier study.     

Reproductive impairment of sea urchins upon chronic exposure to cadmium. Part I: Effects on gamete quality

Successful reproduction is a determining factor for species survival. Pollution may impair reproductive success of adults through effects on gamete quality. Reproductive impairment of the sea urchin Anthocidaris crassispina upon chronic (4 weeks) exposure to 0.01 and 0.1 mg l-1 Cd2+ was investigated. Criteria used for assessing gamete quality included sperm motility, egg morphology, fertilization rate and dynamics of first cleavage. A dose-response relationship was found between Cd2+ levels and changes in sperm motility, and percentage fertilization. Sperm motility, measured by computer-assisted sperm analysis, indicated that percent motile sperm, velocities, and percent sperm with normal trajectory were significantly affected by chronic exposure to > or = 0.1 mg l-1 Cd2+. A decline in sperm motility was also accompanied by a decrease in fertilization success of sea urchin sperm. Width/height ratio of sea urchin eggs was not affected by cadmium, but larger egg sizes were found when sea urchins were exposed to 0.1 mg l-1 Cd2+. Male sea urchins exposed to Cd2+ produced poorer quality sperm, as indicated by a lower percent fertilization and lower cleavage rate, implying that male sea urchins were more sensitive than females to chronic Cd2+ exposure. Results of the present study provide an explanation of reproductive impairment in marine invertebrates upon chronic exposure to Cd2+.     

Subacute effects of a phosphorothionate pesticide on mixed function oxidases of wistar rats

Abstract

Subacute oral toxicity of a newly developed phosphorothionate insecticide (2‐butenoic acid‐3‐(diethoxy‐phosphinothioyl) methyl ester), coded as RPR‐2, was studied in male rats by oral (multiple) intubation of low (0.014 mg kg^‐1 day^‐1), medium (0.028 mg kg^‐1 day^‐1), and high (0.042 mg kg^‐1 day^‐1) dose for 90 days. The medium and high dose produced toxic symptoms along‐with some mortality (20%) occurred in the high dose treated rats. The medium and high doses caused significant inhibition in cytochrome P‐450 activity in liver, lung, kidney and brain tissues at 45 and 90 days. The high dose caused significant decrease in cyt.b₅ activity of all the four tissues at 45 and 90 days. Whereas, medium dose brought such effect in liver and lung at 45 and 90 days. Kidney and brain cyt.b₅ activity decreased significantly at 90^th day due to medium dose. Low dose also caused inhibition in cyt.b₅ activity in brain at 90^th day. Cytochrome P‐450 reductase activity was decreased significantly in liver, lung, kidney and brain at 45 and 90^th by the medium and high dose. The results indicated that RPR‐2 had potential to modulate hepatic and extra‐hepatic cyt.P‐450 dependent monooxygenase system of rat due to subacute exposure. These metabolic alterations were quite reversible after 28 days withdrawal of treatment.     

Anomalies on capture nets of Hydropsyche slossonae larvae (Trichoptera; Hydropsychidae) following a sublethal chronic exposure to cadmium

A laboratory study on the sublethal effects of cadmium (Cd) on the net-spinning process of the larvae of Hydropsyche slossonae was conducted in order to assess the potential of net anomalies as an indicator of chronic exposure to Cd. Two major anomalies with different frequency levels were identified after chronic exposure to 0.37, 1.2, 11.6, 21.4 and 43.3 microg l(-1) of Cd. The first was a distortion of the midline meshes where the diamond-shape structure is disrupted and the meshes are separated by extra strands (called 'midline' anomaly). The second aberration consisted of a distortion of the rectilinear structure of net opening by strands being fused or added over the meshes (called 'crossover' anomaly). The midline distortion may be linked to a physiological stress caused by Cd, which can affect the control of the net-spinning process. It was not possible to relate the crossover aberrations to a specific toxic action of Cd, but data indicated that both anomalies are independent from each other and that two modes of action could be implicated. Protein analyses of capture nets have revealed silk polypeptide modifications at the highest Cd concentration tested, indicating a possible effect of Cd interaction with silk proteins. However, neither a gradient-concentration nor a time-dependent response could be established with both aberration frequencies. Silk protein modifications would rather play a secondary role in the appearance of both net anomalies, and mostly at a high concentration level. Finally, the toxicity curves (EC(50)) show that the sensitivity threshold for both types of aberration ranged from 1 to 5 microg l(-1) which is highly sensitive compared with other sublethal effects of Cd on other macroinvertebrate species. Hence, the use of capture-net anomalies of hydropsychid larvae would represent a valuable indicator of sublethal toxicity induced by Cd and possibly by other metals in running waters.     

Impact of chronic cadmium exposure at environmental dose on escape behaviour in sea bass (Dicentrarchus labrax L.; Teleostei, Moronidae)

The effect of chronic exposure to a low concentration (0.5 microg l(-1)) of cadmium ions was investigated on escape behaviour of sea bass, Dicentrarchus labrax, using video analysis. Observations were also performed on the microanatomy of lateral system neuromasts. When fish were exposed for 4h per day over 8 days to the cadmium ions, most of both types of neuromasts observed remained intact. However, some of them presented damaged sensory maculae. Whereas before cadmium exposure, fish responded positively to nearly all the lateral system stimulations, after exposure they decreased by about 10% their positive responses to stimulations. From the 15th day after the beginning of cadmium exposure, neuromasts presented progressively less damage, cadmium accumulation in gills and scales decreased significantly and fish escape behaviour had recovered. This study presents a new concept in ecotoxicology: using behavioural change to reveal the effects of pollution levels, scarcely detectable by currently used techniques (physiological responses).     

New cytochrome P450 1B1, 1C1, 2Aa, 2Y3, and 2K genes from Chinese rare minnow (Gobiocypris rarus): Molecular characterization,basal expression and response of rare minnow CYP1s and CYP2s mRNA exposed to the AHR agonist benzo[a]pyrene

Cytochrome P450 (CYP450) genes play an important role in catalyzing oxidative metabolism of toxicants. Recently, CYP1 subfamily were discovered and reported in fish, however, little is known regarding the CYP2 isoforms in fish. In the present study, the cDNA fragments of CYP 1B1 and 1C1 and CYP2Aa, 2Y3, and 2K of rare minnow were cloned and exhibited a high amino acid sequence identity compared with their zebrafish orthologs. Basal expression showed CYP1C1 and CYP 2Aa expression were observed in all eight tissues analyzed (liver, gill, intestine, kidney, spleen, brain, skin, and muscle). CYP 1A, and 1B1 expression was found in all tissues except for muscle and skin. However, CYP 2Y3 was expressed in liver, spleen, intestine and muscle whereas CYP 2 K in liver, kidney and intestine. 4 and 100 μg L⁻¹ Benzo[a]pyrene (BaP) induced patterns showed that CYP 1A, 1B1 and 1C1 expression in liver, gill, and intestine was strongly up-regulated (p < 0.05). Furthermore, CYP 2Y3 was strongly induced in liver from BaP treatments (p < 0.05). The high induction on mRNA level of CYP1s and CYP 2Y3 by BaP could be associated with catalyzing detoxification and indicated that CYP2s may also be potential biomarker to screen AHR agonist. The high responsiveness of CYP1 and 2 genes suggested Chinese rare minnow is feasible to screen and assess pollution with AHR agonist.     

氮磷钾和乙二胺四乙酸对镉污染三叶鬼针草的吸收特征研究

超富集植物的筛选是植物修复重金属污染土壤技术的核心内容.采用盆栽试验的方法,研究了Cd胁迫下添加营养元素N、P、K和螯合剂乙二胺四乙酸(EDTA)对三叶鬼针草(Bidens pilosa L.)的生长反应和生理生化特性以及对Cd的吸收积累特征.盆栽试验结果显示,在Cd为10 mg/kg时,添加营养元素N、P、K和EDT...     

Effects of chronic exposure to lead,copper, zinc,and cadmium on biomarkers of the European eel,Anguilla anguilla

Exposure to specific metallic compounds can cause severe deleterious modifications in organisms. Fishes are particularly prone to toxic effects from exposure to metallic compounds via their environment. Species that inhabit estuaries or freshwater environments can be chronically affected by persistent exposure to a large number of metallic compounds, particularly those released by industrial activities. In this study, we exposed yellow eels (European eel, Anguilla anguilla) for 28 days to environmentally relevant concentrations of four specific metals; lead (300, 600, and 1,200 μg/l), copper (40, 120, and 360 μg/l), zinc (30, 60, and 120 μg/l) and cadmium (50, 150, and 450 μg/l). The selected endpoints to assess the toxicological effects were neurotransmission (cholinesterasic activity in nervous tissue), antioxidant defense, and phase II metabolism (glutathione-S-transferase [GST] activity, in both gills and liver tissues), and peroxidative damage. The results showed an overall lack of effects on acetylcholinesterase for all tested metals. Lead, copper, and cadmium exposure caused a significant, dose-dependent, increase in GST activity in gill tissue. However, liver GST only significantly increased following zinc exposure. No statistically significant effects were observed for the thiobarbituric acid reactive substances assay, indicating the absence of peroxidative damage. These findings suggest that, despite the occurrence of an oxidative-based response after exposure to lead, copper, and cadmium, this had no consequence in terms of peroxidative membrane damage; furthermore, cholinergic neurotoxicity caused by lead, copper, and cadmium did not occur. The implications of these results are further discussed.     

Effect of a subchronic exposure to Simazine on energetic metabolism of common carp (Cyprinus carpio)

The energetic parameters, such as glycogen, glucose, proteins, lactate and adenosine triphosphate (ATP) content and lactate deshydrogenase (LDH) activity in tissues and blood of carps from simazine (2-chloro-4,6-bis(ethylamino)-s-triazine) contaminated waters were investigated. In order to confirm the field results, a laboratory experiment was designed in which carps were exposed to simazine at the concentration level of 45 μ g. L^{? 1} (10-fold of the amount found in natural waters) for 90 days. Fish from a contaminated reservoir showed low glycogen concentrations in hepatopancreas and muscle, while fish in another contaminated reservoir showed high LDH activity together with an increase in lactate content in muscle. Laboratory findings did not confirm field results, and fish exposed to simazine did not show alterations in the parameters studied. The results suggest that carps were not stressed by the presence of the simazine at the concentration levels found in both studies and the mechanisms of defense covered the energetic demand.     

多壁碳纳米管短期作用对厌氧颗粒污泥的影响

研究了不同质量浓度（1、20和100 mg·L-1） 多壁碳纳米管（multiwalled carbon nanotubes,MWCNTs） 短期（7 d） 作用对厌氧污泥系统的影响。结果表明：1、20和100 mg·L-1的 MWCNTs反应器出水中的COD、pH、VFA与对照组变化规律一致;其中,100 mg·L-1的MWCNTs可以诱导更快的底物利用率。不同质量浓度MWCNTs反应器的产气量和甲烷体积分数与对照组之间相比无显著差异（P>0.05）。运用修正Gompertz 方程拟合甲烷产量曲线以及计算最大比产甲烷速率（Umax,CH4）和最大比COD去除速率（Umax,COD）表明厌氧产甲烷菌产气特性没有受到MWCNTs的影响。实验研究结果为以后研究碳纳米管在厌氧废水处理中的影响提供了提供新的思路和方法。     

Effect of clay and organic matter type on the ecotoxicity of zinc and cadmium to the potworm Enchytraeus albidus

Clay and organic matter are considered as important parameters influencing bioavailability and ecotoxicity of metals in soils. As there exists a large variation in the type of clay and organic matter in field soils, the quantity of these variables alone may not be good indicators of metal bioavailability. To test this hypothesis, toxicity experiments with the potworm Enchytraeus albidus were conducted in artificial soils with three types of clay and seven types of organic matter, while the soil pH was kept constant. The 14d LC₅₀ of zinc and cadmium varied from 83.0 to 1140 mg Zn/kg D.W. and from 55.2 to 704 mg Cd/kg D.W., respectively, depending on the type of clay and organic matter that were used. Simultaneous measurements of the cation exchange capacity showed that this soil parameter is a better indicator of the bioavailability as it takes into account the type of clay and organic matter as well as other adsorption phases such as metal oxyhydroxides.     

Effect of individual parameter changes on the outcome of the estimated short-term dietary exposure to pesticides

ABSTRACT

In 2015 a scientific workshop was held in Geneva, where updating the International Estimate of Short-Term Intake (IESTI) equations was suggested. This paper studies the effects of the proposed changes in residue inputs, large portions, variability factors and unit weights on the overall short-term dietary exposure estimate. Depending on the IESTI case equation, a median increase in estimated overall exposure by a factor of 1.0-6.8 was observed when the current IESTI equations are replaced by the proposed IESTI equations. The highest increase in the estimated exposure arises from the replacement of the median residue (STMR) by the maximum residue limit (MRL) for bulked and blended commodities (case 3 equations). The change in large portion parameter does not have a significant impact on the estimated exposure. The use of large portions derived from the general population covering all age groups and bodyweights should be avoided when large portions are not expressed on an individual bodyweight basis. Replacement of the highest residue (HR) by the MRL and removal of the unit weight each increase the estimated exposure for small-, medium- and large-sized commodities (case 1, case 2a or case 2b equations). However, within the EU framework lowering of the variability factor from 7 or 5 to 3 counterbalances the effect of changes in other parameters, resulting in an estimated overall exposure change for the EU situation of a factor of 0.87-1.7 and 0.6-1.4 for IESTI case 2a and case 2b equations, respectively.