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Results for “xenobiotic detoxification”

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PubMed2026

Functional analysis of down-regulated CYP6AE gene clusters involved in the insecticidal mechanism of lycorine against Spodoptera litura.

BACKGROUND: Plants have evolved abundant defensive secondary metabolites to resist insect herbivores. Lycorine is an alkaloid with insecticidal activity from Amaryllidaceae plants, which the destructive pest Spodoptera litura naturally avoids. Cytochrome P450 enzymes are central to xenobiotic detoxification in insects, but the mechanism by which lycorine acts against S. litura remains unknown. This study aimed to reveal the toxic mechanism of lycorine focusing on P450-mediated detoxification. RESULTS: Lycorine exhibited substantial toxicity to first-instar S. litura larvae (LD50 = 0.55 μg larva-1). Subsequently, when fifth-instar larvae were exposed to a sublethal dose (LD30) of lycorine, Lyc disrupted metabolic pathways, damaged Malpighian tubules, and induced oxidative stress. Furthermore, lycorine strongly repressed a CYP6AE gene cluster (CYP6AE47, CYP6AE50, CYP6AE70, CYP6AE138 and CYP6AE139) and decreased total P450 activity to 45% in the Malpighian tubules. RNAi co-silencing of these cluster genes increased larval mortality (+30%) under lycorine treatment. Finally, molecular docking and microscale thermophoresis analyses further confirmed direct binding between Lyc and this CYP6AE gene cluster, with the strongest affinity observed for CYP6AE47 (Kd = 518.5 nM). A key residue, ARG170, may be vital for the interaction between Lyc and CYP6AE47. CONCLUSIONS: These results demonstrate that the insecticidal mechanism of Lyc involves suppressing the expression and function of a CYP6AE gene cluster, thereby impairing detoxification capacity, which leads to Lyc accumulation and larval mortality. Elucidation of the detoxification system-targeted mechanism for this plant-derived compound provides a foundation for developing novel, sustainable pest management strategies against S. litura and potentially other noctuid pests. © 2026 Society of Chemical Industry.

Animals↗

PubMed2026

The Drosophila aryl hydrocarbon receptor ortholog, spineless, modulates survival and reproduction.

The aryl hydrocarbon receptor (AhR) is a highly conserved, ligand-activated transcription factor in mammals involved in multiple physiological processes, including development, xenobiotic detoxification, and potentially aging, and some of the most potent activators of AhR are tryptophan metabolites. AhR manipulation across species has been shown to have conflicting results on aging phenotypes that are often tissue specific. To expand our understanding of AhR and aging, we studied AhR affects survival and reproduction in Drosophila melanogaster, whose genome contains an ortholog of AhR, spineless (ss). Our findings indicate that ss-deficient flies have a shorter lifespan than wildtype flies but interestingly exhibit reduced mortality until approximately 40 days of age. Similarly, ss-deficient flies are more stress resistant than wildtype at young ages, but this reverses in later age. Negative lifespan-shortening effects of tryptophan metabolites were mitigated in ss-deficient flies, suggesting that the effects of these metabolites are ss-reliant, similar to AhR in mammals. Overall, our preliminary work demonstrates an evolutionarily conserved role for AhR in the aging process and increases our knowledge of the role of AhR/ss on aging phenotypes.

Animals↗

PubMed2025

Systematic identification and characterization of regulators of aryl hydrocarbon receptor signaling.

The human aryl hydrocarbon receptor (AHR) integrates chemical signals derived from the environment, gut microbes, and endogenous sources to regulate processes ranging from intestinal barrier integrity to xenobiotic detoxification. Despite strong evidence that dysregulation of AHR signaling is a causal factor in metabolic and autoimmune disorders, we currently lack a comprehensive understanding of the factors that regulate AHR activity in human cells. Here, we use genome-scale CRISPR screening to systematically identify regulators of AHR signaling in hepatocytes. The resulting datasets recapitulate the core AHR signaling pathway and identify a large network of regulators. Many of these factors have roles beyond AHR signaling, reflecting that AHR signaling is deeply integrated into human cell biology. We further dissect this network to reveal novel modes of regulation of AHR expression, protein levels, and signaling. For example, we find that the E3 ubiquitin ligase UBR5 sustains AHR signaling by counteracting degradation of ligand-bound AHR. Finally, we identify components of the AHR regulatory network that are specific to cell types and ligands as potential nodes to manipulate AHR signaling in a targeted manner for therapeutic benefit. Overall, our results define the regulatory network that underpins AHR activation, with implications for our understanding of host-microbe interactions and integrative chemosensation and the etiology of metabolic and inflammatory disorders.

Journal Article↗

PubMed2024

UDP-glycosyltransferases act as key determinants of host plant range in generalist and specialist Spodoptera species.

Phytophagous insects have evolved sophisticated detoxification systems to overcome the antiherbivore chemical defenses produced by many plants. However, how these biotransformation systems differ in generalist and specialist insect species and their role in determining insect host plant range remains an open question. Here, we show that UDP-glucosyltransferases (UGTs) play a key role in determining the host range of insect species within the Spodoptera genus. Comparative genomic analyses of Spodoptera species that differ in host plant breadth identified a relatively conserved number of UGT genes in generalist species but high levels of UGT gene pseudogenization in the specialist Spodoptera picta. CRISPR-Cas9 knockouts of the three main UGT gene clusters of Spodoptera frugiperda revealed that UGT33 genes play an important role in allowing this species to utilize the poaceous plants maize, wheat, and rice, while UGT40 genes facilitate utilization of cotton. Further functional analyses in vivo and in vitro identified the UGT SfUGT33F32 as the key mechanism that allows generalist S. frugiperda to detoxify the benzoxazinoid DIMBOA (2,4-dihydroxy-7-methoxy-2H-1,4-benzoxazin-3(4H)-one), a potent insecticidal phytotoxin produced by poaceous plants. However, while this detoxification capacity is conserved in several generalist Spodoptera species, Spodoptera picta, which specializes on Crinum plants, is unable to detoxify DIMBOA due to a nonfunctionalizing mutation in SpUGT33F34. Collectively, these findings provide insight into the role of insect UGTs in host plant adaptation, the mechanistic basis of evolutionary transitions between generalism and specialism and offer molecular targets for controlling a group of notorious insect pests.

Animals↗

PubMed1978

The role of cytochrome P-450 in the toxicity of xenobiotics.

The cytochrome P-450 containing mixed-function oxidase system bound to the ergastoplasmic membrane plays an essential role both in the detoxification as well as in the activation of numerous xenobiotics. In many cases, this enzyme system initiates the formation of reactive electrophilic intermediates (epoxides, free radicals, carbenes) which may induce cytotoxic, mutagenic and carcinogenic effects by reacting with various cell constituents. In most cases, the active metabolites are covalently bound to the proteins and nucleic acids, but the binding to lipids or the initiation of the lipid peroxidation is also important. In the activation of xenobiotics by N-hydroxylation or N-dealkylation an aminoxidase is of special importance which is independent of cytochrome P-450. The intermediates arising from this enzyme reaction frequently become biologically active only after being stabilized by an ester bond.

Aflatoxins↗

PubMed1979

Phenol sulfotransferases.

Two phenol sulfotransferases have been purified from rat liver by conventional techniques coupled with affinity chromatography on Affi-Gel blue and ATP-agarose. Both enzymes are homogeneous by the criterion of sodium dodecyl sulfate gel electrophoresis. Each enzyme has a molecular weight of approximately 65,000 and consists of two subunits of apparently equal size. The enzymes are also similar in specificity and in their kinetic parameters but differ in amino acid composition and in their elution from DEAE-cellulose. With adenosine 3'-phosphate 5'-phosphosulfate as donor, a large variety of phenolic compounds serve as sulfate acceptor; sterols, simple alcohols, bile acids, and hydroxamates do not serve as substrates. The transferases may be considered as detoxification enzymes which catalyze the conjugation of xenobiotics containing a phenol group or of phenolic compounds generated by endogenous oxidation. The enzymes act on 3-hydroxyindole to yield indican, suggesting that their in vivo function may include the production of this normal tryptophan metabolite.

Amino Acids↗

PubMed1979

Biotransformation of xenobiotics in human intestinal mucosa.

Drug-metabolizing enzymes, especially monooxygenases, play a major role in biotransformation and detoxification of many foreign compounds including environmental carcinogens. Although largely localized in the liver they are also found in the small intestine, which is the portal of entry of dietary toxins. Therefore cytochrome P-450 content as well as monooxygenase (7-ethoxycoumarin O-deethylase) and NADPH-cytochrome c reductase activities were determined in surgical specimens of the human small intestine and in jejunal biopsy material obtained from patients by use of a hydraulic biopsy instrument. Microsomes were prepared from surgical material; these ranged in P-450 content from 30 to 120 pmole/mg protein and in monooxygenase activity from 60 to 110 pmole/min-mg protein. In the 20,000g supernatant of the homogenized biopsy material, monooxygenase activity was undetectable in patients who had total villous atrophy, and low enzyme rates were found when the mucosa showed a partial villous atrophy. The mucosal monooxygenase activity of patients with normal jejunal histology and steatorrhea was significantly higher than in mucosa with villous atrophy but was only half of that observed in normal controls. These eight control patients had normal histology and no malassimilation. Our results suggest that monooxygenase activity in the human small intestine is dependent on the morphological integrity of the mucosa and that in normal mucosa the enzyme rates are reduced when malassimilation is present.

Animals↗

PubMed1978

Effect of trichlorophenols on xenobiotic metabolism in the rat.

Unlike halogenated benzenes, trichlorophenols did not induce xenobiotic metabolism in the rat. 2,3,5-, 2,3,6-, 2,4,5-, and 2,4,6-Trichlorophenol at doses as high as 400 mg/kg p.o. daily for 14 days did not alter EPN detoxification. Only 2,4,5-trichlorophenol at the highest dose decreased microsomal NADPH-cytochrome c reductase activity and cytochrome P-450 content. In vitro, all 4 isomers inhibited EPN detoxification and the demethylation of p-nitroanisole. UDP-glucuronyltransferase was not altered in vivo and was only slightly inhibited in vitro by 2,3,5- and 2,4,5-trichlorophenol. The compounds were not hepatotoxic as assessed by measurement of hepatic glucose-6-phosphatase and serum sorbitol dehydrogenase.

Animals↗