Abstract:
:Studies were undertaken to investigate the mechanism of bioactivation and covalent binding of TNT. Incubation of [14C]TNT with rat liver microsomes in the presence of an NADPH generating system resulted in metabolism and covalent binding to microsomal proteins. Time-dependence studies showed that TNT was rapidly reduced to yield 4-hydroxylamino-2,6-dinitrotoluene (4HA), 4-amino-2,6-dinitrotoluene (4A) and 2-amino-4,6-dinitrotoluene (2A) as intermediates which were further metabolized to form 2,4-diamino-6-nitrotoluene (2,4DA) and 2,6-diamino-4-nitrotoluene (2,6DA). In contrast to the rapid disappearance of TNT, formation of covalent protein adducts increased with time, suggesting that the reactive intermediate was likely to be formed not directly from TNT but from proximal intermediates such as 4HA. The hypothesis that 4HA was more readily converted to the reactive intermediate than TNT was further supported by the increased levels of covalent adduct formation when [14C]4HA was incubated directly with liver microsomes. Covalent binding of TNT and 4HA was dependent on oxygen concentration. Higher levels of covalent adducts were formed when TNT was incubated aerobically (up to 50% oxygen concentration) than under anaerobic conditions. Covalent binding of [14C]4HA also increased with increasing oxygen concentrations. These results suggest that the reactive intermediate is likely to be an oxidized metabolite of 4HA, e.g. 4-nitroso-2,6-dinitrotoluene. Compounds containing a free sulfhydryl group (cysteine, N-acetylcysteine, GSH or 3,4-dichlorobenzenethiol) decreased the amount of covalent binding to various degrees, suggesting the involvement of the sulfhydryl group in adduct formation with TNT following bioactivation. Metabolic activation of TNT by liver microsomes required NADPH but not NADH as the cofactor. Incubation of [14C]TNT with purified rat liver NADPH cytochrome P450 reductase under either aerobic or anaerobic conditions yielded exclusively 4HA. In contrast, 2A and 4A were formed following incubation of TNT with the reconstituted system containing cytochrome P450, NADPH cytochrome P450, reductase and dilauroyl phosphatidylcholine. These observations suggest that the initial reduction of the nitro group can be catalyzed by NADPH cytochrome P450 reductase alone but cytochrome P450 is needed in the reduction of the hydroxylamine to the amine.
journal_name
Chem Biol Interactjournal_title
Chemico-biological interactionsauthors
Leung KH,Yao M,Stearns R,Chiu SHdoi
10.1016/0009-2797(94)03606-9subject
Has Abstractpub_date
1995-06-30 00:00:00pages
37-51issue
1eissn
0009-2797issn
1872-7786pii
0009279794036069journal_volume
97pub_type
杂志文章abstract::Oxidative stress is a cellular or physiological condition of elevated concentrations of reactive oxygen species that cause molecular damage to vital structures and functions. Several factors influence the susceptibility to oxidative stress by affecting the antioxidant status or free oxygen radical generation. Here, we...
journal_title:Chemico-biological interactions
pub_type: 杂志文章,评审
doi:10.1016/0009-2797(96)03729-5
更新日期:1996-09-27 00:00:00
abstract::Nuclear receptor activation in liver leads to coordinated alteration of the expression of multiple gene products with attendant phenotypic changes of hepatocytes. Peroxisome proliferators including endogenous fatty acids, environmental chemicals, and drugs induce a multi-enzyme metabolic response that affects lipid an...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/j.cbi.2013.11.006
更新日期:2014-02-25 00:00:00
abstract::20(S)-protopanaxadiol (PPD) possesses various biological properties, including anti-inflammatory, antitumor and anti-fatigue properties. Recent studies found that PPD functioned as a neurotrophic agent to ameliorate the sensory deficit caused by glutamate-induced excitotoxicity through its antioxidant effects and exhi...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/j.cbi.2017.11.008
更新日期:2018-01-05 00:00:00
abstract::Alcohol dehydrogenase 3 (ADH3) has emerged as an important regulator of protein S-nitrosation in its function as S-nitrosoglutathione (GSNO) reductase. GSNO depletion is associated with various disease conditions, emphasizing the potential value of a specific ADH3 inhibitor. The present study investigated inhibition o...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/j.cbi.2009.01.008
更新日期:2009-06-15 00:00:00
abstract::The human T-cell leukemia virus type I (HTLV-1) is the causative agent of adult T-cell leukemia (ATL), an aggressive CD4-positive T-cell neoplasia. The HTLV-1 proto-oncogene Tax, a potent transcriptional activator of cellular and viral genes, is thought to play a pivotal role in the transforming properties of the viru...
journal_title:Chemico-biological interactions
pub_type: 杂志文章,评审
doi:10.1016/j.cbi.2010.06.005
更新日期:2010-11-05 00:00:00
abstract::Dietary flavonoid quercetin has been suggested as a cancer chemopreventive agent, but the mechanisms of action remain unclear. This study investigated the influence of quercetin on p38-MAPK and the potential regulation of the nuclear transcription factor erythroid-2p45-related factor (Nrf2) and the cellular antioxidan...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/j.cbi.2011.12.005
更新日期:2012-01-25 00:00:00
abstract::By rapid hydrolysis of the neurotransmitter, acetylcholine, acetylcholinesterase terminates neurotransmission at cholinergic synapses. Acetylcholinesterase is a very fast enzyme, functioning at a rate approaching that of a diffusion-controlled reaction. The powerful toxicity of organophosphate poisons is attributed pr...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/j.cbi.2010.01.042
更新日期:2010-09-06 00:00:00
abstract::Andrographolide (Andro), a diterpenoid lactone isolated from a traditional herbal medicine Andrographis paniculata, is known to possess multiple pharmacological activities. In our previous study, Andro had been shown to have potent anti-cancer activity against human colorectal carcinoma Lovo cells by inhibiting cell-c...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/j.cbi.2009.04.011
更新日期:2009-08-14 00:00:00
abstract::Evidence for the reversible binding of paraquat to calf thymus DNA has been obtained using equilibrium dialysis and thermal melting point determinations. The data indicated the presence of at least two populations of binding site with affinity constants of 6.2 X 10(4) and 7.1 X 10(3) M-1, respectively. The binding cap...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/0009-2797(87)90035-4
更新日期:1987-02-01 00:00:00
abstract::The effect of repeated parenteral administration of cadmium (0.75, 1.5 and 3.0 mg/kg) on tissue disposition and urinary excretion of cadmium, zinc, copper and iron has been studied in the male rat. Cadmium, zinc and copper accumulated in liver and kidney, but the concentration of iron did not alter significantly. The ...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/0009-2797(79)90137-6
更新日期:1979-10-01 00:00:00
abstract::Stearoyl-CoA desaturase (SCD) generates monounsaturated fatty acids (MUFAs) which contribute to cell growth, survival, differentiation, metabolic regulation and signal transduction. Overexpression of SCD is evident and implicated in metabolic diseases such as diabetes and non-alcoholic fatty liver disease. SCD also st...
journal_title:Chemico-biological interactions
pub_type: 杂志文章,评审
doi:10.1016/j.cbi.2019.108917
更新日期:2020-01-25 00:00:00
abstract::Two new flavonoids, bismilachinone (11) and smilachinin (14), were isolated from the leaves of Smilax china L. together with 14 known compounds. Their structures were elucidated using spectroscopic methods. The PTP1B, α-glucosidase, and DPP-IV inhibitory activities of compounds 1-16 were evaluated at the molecular lev...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/j.cbi.2016.04.012
更新日期:2016-06-25 00:00:00
abstract::Treatment of a lysosome-rich fraction from liver with 2-chloroethylethyl sulfide resulted in a dose-dependent release of arylsulfatase. The inclusion of Ca2+ enhanced the enzyme release by approximately 2.3-fold. The enhancing effect of Ca2+, showing an EC50 value of 30 mM, was mimicked by neither Mg2+ nor Mn2+. Studi...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/0009-2797(95)03618-v
更新日期:1995-08-18 00:00:00
abstract::Butyrylcholinesterase (BChE) is coded by the BCHE gene that presents four exons. The non-codifying exon 1 presents two variants -116G and -116A, being -116A preferentially in cis conformation with the 539T variant (K) of exon 4 which was associated with lower BChE activity and lower body mass index (BMI) variance. Thi...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/j.cbi.2008.04.019
更新日期:2008-09-25 00:00:00
abstract::Postmenopausal osteoporosis is characterized by a reduction in the number of sinusoidal and arterial capillaries in the bone marrow and reduced bone perfusion. Thus, osteogenesis and angiogenesis are coupled in the process of osteoporosis formation and fracture healing. Naringin is the main ingredient of the root Rhiz...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/j.cbi.2016.10.020
更新日期:2017-01-05 00:00:00
abstract::HPV infections in the oral cavity that progress to cancer are on the increase in the USA. Model systems to study co-factors for progression of these infections are lacking as HPVs are species-restricted and cannot grow in preclinical animal models. We have recently developed a mouse papillomavirus (MmuPV1) oral mucosa...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/j.cbi.2020.109321
更新日期:2021-01-05 00:00:00
abstract::Quantum dots (QDs) are highly promising nanomaterials in bioimaging system because of their bright fluorescence, broad UV excitation, narrow emission band, and high photostability. Recently, there is a great activity on Ag2S quantum dots for both imaging and drug/gene delivery due to the potential of having a better c...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/j.cbi.2018.06.032
更新日期:2018-08-01 00:00:00
abstract::Human serum paraoxonase/arylesterase (PON1, EC 3.1.8.1.) is a calcium-dependent enzyme which hydrolyzes a wide variety of organophosphates, including paraoxon, DFP, sarin and soman. Although the 3-D structure of PON has not yet been determined and its sequence shows no similarity with any other crystallized proteins, ...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/s0009-2797(99)00015-0
更新日期:1999-05-14 00:00:00
abstract::Human carbonyl reductases 1 and 3 (CBR1 and CBR3) are monomeric NADPH-dependent enzymes of the short-chain dehydrogenase/reductase superfamily. Despite 72% identity in primary structure they exhibit substantial differences in substrate specificity. Recently, the endogenous low molecular weight S-nitrosothiol S-nitroso...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/j.cbi.2011.01.016
更新日期:2011-05-30 00:00:00
abstract::The development of alcoholic liver diseases depends on the ability of hepatocyte to proliferate and differentiate in the case of alcohol-induced injury. Our previous work showed an inhibitory effect of alcohol on hepatocyte proliferation. However, the effect of alcohol on hepatocyte differentiation has not yet been pr...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/j.cbi.2013.08.016
更新日期:2013-11-25 00:00:00
abstract::The goal of this research was to test the hypothesis that bioactivation reactions could be exploited to deliver and activate mitochondria-targeted antioxidant prodrugs. The concept that bioactivation reactions could be used for prodrug delivery and activation has received little attention. Most bioactivation reactions...
journal_title:Chemico-biological interactions
pub_type: 杂志文章,评审
doi:10.1016/j.cbi.2010.10.004
更新日期:2011-06-30 00:00:00
abstract::Oxidative stress is a major cause of drug induced hepatic diseases. The present study aims to investigate the antioxidative signaling mechanism of a protein isolated from the herb, Cajanus indicus against acetaminophen induced necrotic cell death. We found that incubation of hepatocytes with the protein prevented acet...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/j.cbi.2008.09.006
更新日期:2009-01-27 00:00:00
abstract::Organophosphate (OP) based pesticides are highly toxic compounds that are still widely used in agriculture around the world. According to World Health Organization (WHO) data, it is estimated that between 250,000 and 370,000 deaths occur yearly around the globe as a result of acute intoxications by pesticides. Current...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/j.cbi.2016.05.034
更新日期:2016-11-25 00:00:00
abstract::Arthritis is one of the most prevalent chronic inflammatory diseases, and it is characterized by structural and biochemical changes in major tissues of the joint, including degradation of the cartilage matrix, insufficient synthesis of extracellular matrix (ECM). Ecklonia cava (EC) is a member of the family of Laminar...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/j.cbi.2009.01.006
更新日期:2009-05-15 00:00:00
abstract::Methylmercury is a widely distributed environmental toxicant with detrimental effects on the developing and adult nervous system. Due to its accumulation in the food chain, chronic exposure to methylmercury via consumption of fish and sea mammals is still a major concern for human health, especially developmental expo...
journal_title:Chemico-biological interactions
pub_type: 杂志文章,评审
doi:10.1016/j.cbi.2010.04.007
更新日期:2010-11-05 00:00:00
abstract::A novel post-addition method, based on the trapping of ABTS-radicals, is applied for studying the total antioxidant capacity of seminal plasma. A remarkable profile is observed, in which seminal plasma quenches radicals in a continuous, relatively slow fashion. Five putative antioxidants present in seminal plasma were...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/s0009-2797(00)00179-4
更新日期:2000-07-03 00:00:00
abstract::Glucuronide conjugates represent one of the major types of naturally occurring phase 2 metabolites of xenobiotics and endobiotics. The process underlying their formation, glucuronidation, is normally considered detoxifying, because glucuronides usually possess less intrinsic biological or chemical activity than their ...
journal_title:Chemico-biological interactions
pub_type: 杂志文章,评审
doi:10.1016/s0009-2797(00)00198-8
更新日期:2000-12-01 00:00:00
abstract::The in vivo metabolite patterns of 2,5-difluoroaminobenzene and of its nitrobenzene analogue, 2,5-difluoronitrobenzene, were determined using 19F NMR analysis of urine samples. Results obtained demonstrate significant differences between the biotransformation patterns of these two analogues. For the aminobenzene, cyto...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/0009-2797(94)03317-2
更新日期:1995-01-01 00:00:00
abstract::The present study shows the existence of both Ca2+-dependent and EDTA-resistant hydrolysing activities against HDCP and paraoxon in the particulate and soluble fractions of hen, rat and rabbit liver. HDCP was more extensively hydrolysed than paraoxon in both subcellular fractions and each of three individuals of the t...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/s0009-2797(99)00035-6
更新日期:1999-05-14 00:00:00
abstract::Notwithstanding ongoing progress in anticancer therapeutics development, the persistent problem remains to selectively target tumors while sparing normal tissues. This is confounding largely because the differences between normal and tumor cells are often subtle and part of a gradient, where a gene product may be more...
journal_title:Chemico-biological interactions
pub_type: 杂志文章,评审
doi:10.1016/s0009-2797(97)00166-x
更新日期:1998-04-24 00:00:00