Hepatic CYP3A4,SULT2A1,and UGT1A1 synergistically mediate metabolic detoxification of genipin

In the present study,we aimed to ascertain the metabolic detoxification routes of genipin via CYP3A4,SULT2 A1,and UGT1 A1 in Hepa RG cells.It was found that the hepatic CYP3A4,SULT2 A1,and UGT1 A1 synergistically mediated the metabolic detoxification of genipin,and the CYP3A4 was the limited enzyme.In detail,the pivotal detoxification pathway was CYP3A4-SULT2 A1/UGT1 A1,indicating that SULT2 A1 and UGT1 A1 further catalyzed the phase II detoxification metabolism followed by the genipin metabolization by CYP3A4 to the phase I metabolites with alleviated toxicity.Our findings provided valuable cues for future studies on the detoxification of genipin,even the compatibility detoxification of Zhi-zi.Moreover,these data facilitated the development and rational administration of genipin and Zhi-zi.

Age-related Metabolic Effects of Acetaldehyde on Rats With Reference to Detoxification Enzymes and Sulfhydryl Groups

Induced-acetaldehyde toxic effects on gluatathione [GSH] metabolism and sulfhydryl (SH) groups in liver and in brain of female albino rats with reference to age was studied.The total -SH groups were decreased whereas the specific activities of glutathione-S-transferase [GST] and glutathione peroxidase [GP0] were increased in acetaldehyde treated rats. However, the specific activity levels of glutathione reductase [GR] and Γ-glutamylcysteine synthetase [Γ-GCS] were decreased. In general, acetaldehyde indueed changes in the specific activities of the enzymes that increase with increasing age

Novel insights into conjugation of antitumor-active unsymmetrical bisacridine C-2028 with glutathione:Characteristics of non-enzymatic and glutathione S-transferase-mediated reactions

Unsymmetrical bisacridines(UAs) are a novel potent class of antitumor-active therapeutics.A significant route of phase II drug metabolism is conjugation with glutathione(GSH),which can be non-enzymatic and/or catalyzed by GSH-dependent enzymes.The aim of this work was to investigate the GSHmediated metabolic pathway of a representative UA,C-2028.GSH-supplemented incubations of C-2028 with rat,but not with human,liver cytosol led to the formation of a single GSH-related metabolite.Interestingly,it was also revealed with rat liver microsomes.Its formation was NADPH-independent and was not inhibited by co-incubation with the cytochrome P450(CYP450) inhibitor 1-aminobenzotriazole.Therefore,the direct conjugation pathway occurred without the prior CYP450-catalyzed bioactivation of the substrate.In turn,incubations of C-2028 and GSH with human recombinant glutathione S-transferase(GST) P1-1 or with heat-/ethacrynic acid-inactivated liver cytosolic enzymes resulted in the presence or lack of GSH conjugated form,respectively.These findings proved the necessary participation of GST in the initial activation of the GSH thiol group to enable a nucleophilic attack on the substrate molecule.Another C-2028-GSH S-conjugate was also formed during non-enzymatic reaction.Both GSH S-conjugates were characterized by combined liquid chromatography/tandem mass spectrometry.Mechanisms for their formation were proposed.The ability of C-2028 to GST-mediated and/or direct GSH conjugation is suspected to be clinically important.This may affect the patient’s drug clearance due to GST activity,loss of GSH,or the interactions with GSH-conjugated drugs.Moreover,GST-mediated depletion of cellular GSH may increase tumor cell exposure to reactive products of UA metabolic transformations.

Insecticide resistance status and biochemical mechanisms involved in Aedes mosquitoes: A scoping review

Mosquitoes belonging to the genus Aedes pose a significant threat to human health on a global scenario due to their role in transmission of dengue,chikungunya,zika,and yellow fever.In absence of specific medications and vaccines against these diseases,disease prevention relies on vector control.However,in today’s world,vector control is facing major challenges due to the onset of insecticide resistance in mosquitoes.There are four main mechanisms of insecticide resistance,namely,behavioral resistance,reduced penetration/cuticular resistance,metabolic detoxification,and target site resistance;however,the latter two mechanisms have been studied widely in Aedes mosquitoes.Insecticide resistance in Aedes mosquitoes is widespread throughout the world.This review compiles the degree of insecticide resistance/susceptibility prevailing among different field populations of Aedes mosquitoes worldwide.In addition,the review has detailed the mechanisms providing the resistance phenomenon observed in nature in Aedes mosquitoes.

Cardinium infection alters cotton defense and detoxification metabolism of its whitefly host

Field monitoring revealed that the infection ratio of the bacterial symbiont Cardinium in the whitefly(Bemisia tabaci MED)was relatively low in northern China.However,the role of this symbiont and the symbiont-whitefly-host plant interaction mechanism are poorly understood.We investigated the influence of Cardinium on the competitiveness of the host whitefly and the physiological interaction between the host plants and host whiteflies.Cardinium-infected whiteflies were displaced by uninfected whiteflies after 5 generations,which showed that Cardinium infection reduced whitefly competitiveness.The defense response genes of cotton significantly decreased under infestation by infected whiteflies compared to uninfected whiteflies.The expression of detoxification metabolism genes,especially the uridine 5ʹ-diphospho-glucuronyltransferase and P450 genes,in infected whiteflies significantly decreased.These results demonstrated that Cardinium could inhibit the defense response of the host plant and decrease the detoxification metabolism ability of the host whitefly.The reduced competitiveness of infected whiteflies may be associated with the inhibition of the whitefly detoxification metabolism by Cardinium,resulting in the reduced performance of infected whiteflies.However,Cardinium infection can suppress plant defenses,which may benefit both infected and uninfected whiteflies when they coexist.This research illustrates the symbiont–whitefly–host plant interaction mechanism and the population dynamics of the whitefly.

The genome sequence of a spider mite,Tetranychustruncatus, provides insights into interspecific host rangevariation and the genetic basis of adaptation to a low-qualityhost plant

The phytophagous miteTetranychus truncatusis a serious pest in East Asiabut has a relatively narrower host range than the pest miteTetranychus urticae,which canfeed on over 1200 plant species.Here,we generated a high-quality chromosomal levelgenome ofT.truncatusand compared it with that ofT.urticae,with an emphasis on thegenes related to detoxification and chemoreception,to explore the genomic basis under-lying the evolution of host range.We also conducted population genetics analyses(in 86females from 10 populations)and host transfer experiments(in 4 populations)to investi-gate transcription changes following transfer to a low-quality host(Solanum melongena,eggplant),and we established possible connections between fitness on eggplant and genesrelated to detoxification and chemoreception.We found thatT.truncatushas fewer genesrelated to detoxification,transport,and chemoreception thanT.urticae,with a particularlystrong reduction in gustatory receptor(GR)genes.We also found widespread transcrip-tional variation amongT.truncatuspopulations,which varied in fitness on eggplant.Wecharacterized selection on detoxification-related genes throughωvalues and found a nega-tive correlation between expression levels andωvalues.Based on the transcription results,as well as the fitness and genetic differences among populations,we identified genes po-tentially involved in adaptation to eggplant inT.truncatus.Our work provides a genomicresource for this pest mite and new insights into mechanisms underlying the adaptation ofherbivorous mites to host plants.

Repeated exposure of fluazinam fungicides affects gene expression profiles yet carries no costs on a nontarget pest

Fungicides are used to control pathogenic fungi of crop species,but they have also been shown to alter behavioral,life history and fitness related traits of nontarget insects.Here,we tested the fungicide effects on feeding behavior,survival and physiology of the nontarget pest insect,the Colorado potato beetle(CPB)(Leptinotarsa decemlineata).Feeding behavior was studied by a choice test of adult beetles,which were allowed to choose between a control and a fungicide(fluazinam)treated potato leaf.Larval survival was recorded after 24 and 72 h exposure to control and fungicide-treated leaves with 2 different concentrations.The adults did not show fungicide avoidance behavior.Similarly,survival of the larvae was not affected by the exposure to fungicides.Finally,to understand the effects of fungicides at the physiological level(gene expression),we tested whether the larval exposure to fungicide alter the expression of 5 metabolic pathway and stress associated genes.Highest concentration and 72-h exposure caused upregulation of 1 cytochrome P450(CYP9Z14v2)and 1 insecticide resistance gene(Ldace1),whereas metabolic detoxification gene(Ugt1)was downregulated.At 24-h exposure,highest concentration caused downregulation of another common detoxification gene(Gs),while both exposure times to lowest concentration caused upregulation of the Hsp70 stress tolerance gene.Despite these overall effects,there was a considerable amount of variation among different families in the gene expression levels.Even though the behavioral effects of the fungicide treatments were minor,the expression level differences of the studied genes indicate changes on the metabolic detoxifications and stress-related pathways.