Abstract:
:Microsomal and soluble epoxide hydrolase (mEH and sEH) fulfill apparently distinct roles: Whereas mEH detoxifies xenobiotics, sEH hydrolyzes fatty acid (FA) signaling molecules and is thus implicated in a variety of physiological functions. These epoxy FAs comprise epoxyeicosatrienoic acids (EETs) and epoxy-octadecenoic acids (EpOMEs), which are formed by CYP epoxygenases from arachidonic acid (AA) and linoleic acid, respectively, and then are hydrolyzed to their respective diols, the so-called DHETs and DiHOMEs. Although EETs and EpOMEs are also substrates for mEH, its role in lipid signaling is considered minor due to lower abundance and activity relative to sEH. Surprisingly, we found that in plasma from mEH KO mice, hydrolysis rates for 8,9-EET and 9,10-EpOME were reduced by 50% compared to WT plasma. This strongly suggests that mEH contributes substantially to the turnover of these FA epoxides-despite kinetic parameters being in favor of sEH. Given the crucial role of liver in controlling plasma diol levels, we next studied the capacity of sEH and mEH KO liver microsomes to synthesize DHETs with varying concentrations of AA (1-30 μM) and NADPH. mEH-generated DHET levels were similar to the ones generated by sEH, when AA concentrations were low (1 μM) or epoxygenase activity was curbed by modulating NADPH. With increasing AA concentrations sEH became more dominant and with 30 μM AA produced twice the level of DHETs compared to mEH. Immunohistochemistry of C57BL/6 liver slices further revealed that mEH expression was more widespread than sEH expression. mEH immunoreactivity was detected in hepatocytes, Kupffer cells, endothelial cells, and bile duct epithelial cells, while sEH immunoreactivity was confined to hepatocytes and bile duct epithelial cells. Finally, transcriptome analysis of WT, mEH KO, and sEH KO liver was carried out to discern transcriptional changes associated with the loss of EH genes along the CYP-epoxygenase-EH axis. We found several prominent dysregulations occurring in a parallel manner in both KO livers: (a) gene expression of Ephx1 (encoding for mEH protein) was increased 1.35-fold in sEH KO, while expression of Ephx2 (encoding for sEH protein) was increased 1.4-fold in mEH KO liver; (b) Cyp2c genes, encoding for the predominant epoxygenases in mouse liver, were mostly dysregulated in the same manner in both sEH and mEH KO mice, showing that loss of either EH has a similar impact. Taken together, mEH appears to play a leading role in the hydrolysis of 8,9-EET and 9,10-EpOME and also contributes to the hydrolysis of other FA epoxides. It probably profits from its high affinity for FA epoxides under non-saturating conditions and its close physical proximity to CYP epoxygenases, and compensates its lower abundance by a more widespread expression, being the only EH present in several sEH-lacking cell types.
journal_name
Arch Toxicoljournal_title
Archives of toxicologyauthors
Marowsky A,Meyer I,Erismann-Ebner K,Pellegrini G,Mule N,Arand Mdoi
10.1007/s00204-017-2060-4subject
Has Abstractpub_date
2017-11-01 00:00:00pages
3571-3585issue
11eissn
0340-5761issn
1432-0738pii
10.1007/s00204-017-2060-4journal_volume
91pub_type
杂志文章abstract::Many carcinogens and mutagens are electrophilic in nature and will react with nucleophilic sites in protein and nucleic acid. Determination of the extent of formation of these adducts of genotoxic agents with protein provides a practical method of monitoring human exposure and of determining the possible risk associat...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/BF00296978
更新日期:1987-01-01 00:00:00
abstract::A compound was isolated from the urine of workers exposed to carbon disulfide during the production of rayon. The compound was identified as 2-thiothiazolidine-4-carboxylic acid (TTCA) by GC/MS and NMR. A HPLC method for the quantitative determination of TTCA was elaborated and applied to urine samples. The method all...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/BF00297130
更新日期:1981-03-01 00:00:00
abstract::The excretion and biotransformation of [14C] 1,1-dichloroethylene (vinylidene chloride, VDC) after administration of a single oral dose has been investigated in female rats. Seventy-two hours after a dose of 0.5, 5.0, and 50.0 mg/kg, 1.26, 9.70, 16.47%, respectively, are exhaled as unchanged VDC, and 13.64, 11.35, 6.1...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/BF00353707
更新日期:1979-07-11 00:00:00
abstract::The present study was designed to evaluate the effects of chronic fluorosis on the dynamics (including fusion and fission proteins), fragmentation, and distribution of mitochondria in the cortical neurons of the rat brain in an attempt to elucidate molecular mechanisms underlying the brain damage associated with exces...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s00204-012-0942-z
更新日期:2013-03-01 00:00:00
abstract::The possibility that the exposure of the embryo to certain chemical substances can lead to behavioral disturbances is known from human epidemiological studies, e.g., in chronic poisoning with mercury and ethanol. Therefore, efforts are made to develop toxicological techniques with which new behavioral teratogens can b...
journal_title:Archives of toxicology
pub_type: 杂志文章,评审
doi:10.1007/BF00310480
更新日期:1981-09-01 00:00:00
abstract::Initially, mice were pretreated with atropine (17.4 mg/kg; IP) and the oxime reactivator HI-6 (50 mg/kg; IP) 5 min prior to an injection of soman (287 micrograms/kg, SC); approximately 2.1 x LD50 dose). More than 95% of the mice survived this dose of soman with atropine and HI-6 pretreatment. In these survivors of som...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/BF00316438
更新日期:1989-01-01 00:00:00
abstract::Inhalation exposure to toluene diisocyanate (TDI) can result in a variety of airway diseases. Concern has been expressed that a putative carcinogenic potential of TDI exists as a result of the formation of toluenediamine (TDA) by hydrolysis of the isocyanate in the body. Results from long-term bioassays (TDI inhalatio...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s002040050094
更新日期:1994-01-01 00:00:00
abstract::A single dose of 10 mg methylmercury chloride per kg body weight was given to 30 days old rats and to adult rats (180-200g)(. This resulted in brain levels of 1.4-2.2 micrograms Hg/g wet weight. In the young rats electron microscopic morphometry showed swelling of the granule cells. The extent of changes was more pron...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/BF00332352
更新日期:1981-04-01 00:00:00
abstract::Breast cancer is the most commonly diagnosed malignancy in females, the etiology being multifactorial and includes the role of lifestyle exposure to DNA-damaging chemicals such as dietary carcinogens benzo (a) pyrene (BaP) and 2-amino-1-methyl-6-phenylimidazo [4, 5-b] pyridine (PhIP). Both compounds require cytochrome...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s00204-019-02558-8
更新日期:2019-10-01 00:00:00
abstract::Occupational and environmental asbestos exposure is the main determinant of malignant pleural mesothelioma (MPM), however, the mechanisms by which its fibres contribute to cell toxicity and transformation are not completely clear. Aberrant DNA methylation is a common event in cancer but epigenetic modifications involv...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s00204-018-2179-y
更新日期:2018-05-01 00:00:00
abstract::The studies presented were designed to investigate the effects of cytochrome P450 inhibition on tetrahydrofuran-induced hepatocellular proliferation in female B6C3F(1) mice. Groups of female B6C3F(1) mice were exposed to dynamic atmospheres containing tetrahydrofuran (THF) concentrations of 0, 5,400 or 15,000 mg/m(3) ...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s00204-003-0474-7
更新日期:2003-08-01 00:00:00
abstract::The cholestatic effect of the newly developed oestradiol sulphamate (J995) was compared with that of the natural oestrogen oestradiol (E) and of the cholestatic standard oestrogen ethinyloestradiol (EE). Female ovariectomized rats were orally treated for 7 days with oestrogen doses molar equivalent to 0.01, 0.1, 1, an...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s002040050409
更新日期:1997-01-01 00:00:00
abstract::Previous rat toxicity studies of alpha-glycosyl isoquercitrin (AGIQ), a water-soluble flavonol glycoside derived from rutin, revealed systemic yellow bone discoloration. This investigative study was conducted to determine the AGIQ metabolite(s) responsible for the discoloration. Female Sprague-Dawley rats were adminis...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s00204-020-02760-z
更新日期:2020-07-01 00:00:00
abstract::Metabolism of carbaryl by rat liver and skin post-mitochondrial fraction has been measured in the presence and absence of cofactors to promote different metabolic pathways. The metabolic capacity was compared with the metabolism of carbaryl during percutaneous absorption in a static skin diffusion system using a varie...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/BF01973722
更新日期:1991-01-01 00:00:00
abstract::Dose-dependent excretion of p,p'DDE in rats was investigated. p,p'DDE itself was the major excreta in rats. But some o,p'isomer of DDE was detected in feces by GC-MS analysis. The excretion of p,p'DDE after a single administration was modified by its dose level. The time pattern of p,p'DDE excretion agrees well with t...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/BF00332361
更新日期:1982-01-01 00:00:00
abstract::We investigated the influence of the dopamine antagonist haloperidol on the neurotransmitter content in the developing rat brain. Dopamine (DA), serotonin (5-HT) and the corresponding metabolites dopac, HVA and HIAA were determined in the corpus striatum of the rat between day 1 and day 21 pn by HPLC with electro-chem...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/BF01973388
更新日期:1992-01-01 00:00:00
abstract::The ethylene oxide adduct formed on the N-terminal valine in haemoglobin was investigated as a biological monitor of tobacco smoke intake. The modified method developed for the determination of the hydroxyethylvaline adduct (HOEtVal) involved reaction of globin with pentafluorophenyl isothiocyanate, extraction of the ...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/BF00332482
更新日期:1988-01-01 00:00:00
abstract::Morphological changes in mitochondria are observed early in the course of acetaminophen (AA)-induced hepatotoxicity, and mitochondrial dysfunction has been observed both in vivo and in vitro following exposure to AA. This study examined the early effects of AA exposure in vivo on mitochondrial respiration and evaluate...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s002040050043
更新日期:1994-01-01 00:00:00
abstract::The rodenticide tetramethylenedisulfotetramine (TETS) is a potent convulsant (lethal dose in humans 7-10 mg) that is listed as a possible threat agent by the United States Department of Homeland Security. TETS has previously been studied in vivo for toxicity and in vitro in binding assays, with the latter demonstratin...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s00204-017-2089-4
更新日期:2018-02-01 00:00:00
abstract::A wide variety of immunosuppressive effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in experimental animals has been documented. In contrast, the impact of dioxin on the human immune system remains controversial, although adverse health effects have been reported in humans after occupational or accidental exposu...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s002040050072
更新日期:1994-01-01 00:00:00
abstract::The amphetamine-derived designer drugs have been illegally used worldwide as recreational drugs, some of which are known to be hepatotoxic in humans. To compare their cytotoxic effects, 3,4-methylenedioxy-N-methamphetamine (MDMA) and its related analogues, N-methyl-1-(3,4-methylenedioxyphenyl)-2-butanamine (MBDB), 3,4...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s00204-008-0323-9
更新日期:2009-01-01 00:00:00
abstract::Using male ICR mice, the LC50 and acute and subacute inhalation toxicity of dichlorosilane (SiH2Cl2, DCS) and the fate of DCS released into the air were investigated. DCS resolved and minute particles including silicon and chloride were observed, when DCS was released into the air. Most particles were under 1 micron i...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s002040050263
更新日期:1996-01-01 00:00:00
abstract::The ultimate purpose of the present study was to evaluate correlations between acute in vivo and in vitro toxicity and log P (P is n-octanol-water partition coefficient). The in vitro toxicity to cloned cells (neuroblastoma N18TG-2 and glioma C6) in culture (ED50) and the in vivo toxicity to mice (LD50) of ethylene gl...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/BF01973634
更新日期:1992-01-01 00:00:00
abstract::DNA damage induced by methylmethane sulfonate, cyclophosphamide, doxorubicin and procarbazine in male germ cells was assessed in rabbits by the demonstration of unscheduled DNA synthesis (UDS), in meiotic and postmeiotic phases of maturation. Immediately after treatment by the intravenous route tritiated thymidine was...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/BF00361252
更新日期:1980-11-01 00:00:00
abstract::The aim of this study was to investigate the electrophilic tissue burden (ETB) formation, assessed as covalent binding of the ultimate carcinogen benzo( a)pyrene diolepoxide (BaPDE) with cellular proteins, in liver, lung and heart, as well as with haemoglobin (Hb) following repeated exposure to binary mixtures of benz...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s00204-003-0518-z
更新日期:2004-02-01 00:00:00
abstract::Retinoids, derivatives of vitamin A, are essential for many vertebrate functions. Furthermore, several drugs of this class of compounds are valuable in the treatment of certain forms of skin disorders and cancer. However, the therapeutic application of retinoids is limited by their teratogenic potency. The limbs are i...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s002040050368
更新日期:1997-01-01 00:00:00
abstract::The metabolism of arsenic is generally accepted to proceed by repetitive reduction and oxidative methylation; the latter is mediated by arsenic methyltransferase (Cyt19). In human urine, the major metabolites of inorganic arsenicals such as arsenite (iAsIII) and arsenate (iAsV) are monomethylarsonic acid (MMA(V)) and ...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s00204-004-0620-x
更新日期:2005-04-01 00:00:00
abstract::Male F344/DuCrj (Fischer) rats were given bisphenol A (BPA) in the diet at levels of 0 (control), 0.25, 0.50 and 1.00%, equivalent to 0, 235, 466 and 950 mg/kg per day, respectively, for 44 days. Body weight gains were depressed dose-dependently in BPA-treated rats, and those of 0.50 and 1.00% groups were significant....
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s002040000204
更新日期:2001-03-01 00:00:00
abstract::The effect of N-benzyl-D-glucamine dithiocarbamate (BGD) on the renal toxicity induced by acute exposure to cadmium-metallothionein (Cd-MT) in rats was studied. Rats were injected intraperitoneally with BGD (400 mumol/kg) 6, 12, or 24 h after intraperitoneal injection of Cd-MT (1.78 mumol Cd as Cd-MT/kg) and thereafte...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/BF01974392
更新日期:1990-01-01 00:00:00
abstract::This study was carried out to investigate the effect of in utero exposure to the cholinotoxicants, nicotine and chlorpyrifos, alone or in combination on neurobehavioral alterations and neuronal morphology latter in adult age. In the present study, 90 days old (corresponding to a human adult age) male and female offspr...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s00204-006-0077-1
更新日期:2006-09-01 00:00:00