• Toxicological Research
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• v.35 no.4
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• pp.303-310
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• 2019

We are exposed to numerous xenobiotic electrophiles on a daily basis through the environment, lifestyle, and dietary habits. Although such reactive species have been associated with detrimental effects, recent accumulated evidence indicates that xenobiotic electrophiles appear to act as signaling molecules. In this review, we introduce our findings on 1) activation of various redox signaling pathways involved in cell proliferation, detoxification/excretion of electrophiles, quality control of cellular proteins, and cell survival during exposure to xenobiotic electrophiles at low concentrations through covalent modification of thiol groups in sensor proteins, and 2) negative regulation of reactive sulfur species (RSS) in the modulation of redox signaling and toxicity caused by xenobiotic electrophiles.

• Journal of Life Science
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• v.13 no.3
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• pp.314-323
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• 2003

The purpose of this study was to examine the effects of xenobiotic nuclear receptors, CAR, SXR, and PPAR${\gamma}$ on the transcriptional activity of estrogen receptor in human breast cancer cell lines and compare with those in human hepatoma cell line. Two different breast cancer cell lines, MCF-7 and MDA-MB-231 were cultured and effects of CAR, SXR, and PPAR${\gamma}$ on the ER-mediated transcriptional activation of synthetic (4ERE)-tk-luciferase reporter gene were analyzed. Consistent with the previous report, CAR significantly inhibited ER-mediated transactivation and SXR repressed modestly whereas the PPAR${\gamma}$ did not repress the ER-mediated transactivation. However, in breast cancer cells neither of the xenobiotic receptors repressed the ER-mediated transactivation. Instead, they tend to increase the transactivation depending on the cell type and xenobiotic nuclear receptors. In MCF-7, SXR but neither CAR nor PPAR${\gamma}$ slightly increased ER-mediated transactivation whereas in MDA-MB-231, CAR and PPAR${\gamma}$ but not SXR tend to increase the transactivation of the reporter gene. These results indicate that the effects of ER cross-talk by the CAR, SXR, and PPAR${\gamma}$ , are different in breast cancer cells from hepatoma cells. In conclusion, the transcriptional regulation by estrogen can involve different cross-talk interaction between estrogen receptor and xenobiotic nuclear receptors depending on the estrogen target cells.

• Korean Journal of Medicinal Crop Science
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• v.14 no.6
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• pp.329-335
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• 2006

The present study was designed to investigate aging-related effects on the activities of xenobiotic metabolizing enzymes of rat liver by dietary supplementation of Korean red ginseng water-extract. Rat did not show any discernible signs of the rejection symptoms, and blood GOT and GPT levels were not influenced by ginseng water extracts, Cytochrome 450 levels and NADPH cytochrome P45O reductase, p-450 dependent ethoxycoumarin O-deethylase, and benzphetamine N-demethylase activities were decreased with aging, however, these phase I system enzymes activities in the ginseng group of24 months were well maintained compared with normal group. But, Levels of cytochrome bs and NADH-cytochrome b$_5$ reductase activities were also decreased with aging and were not found a clear difference between two groups. Glutathione-s-transferase activity, phase II enzyme system, in liver cytosols was also decreased in old ages, but the degree of decrease was higher in normal group than in giuseng supplemented group. These results indicate that long-term supplementation of red ginseng water extracts from weaning to 24 months do not show any side effects to rats, and retard age-related deteriorations of xenobiotic metabolizing enzymes activities in old ages.

• Toxicological Research
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• v.17
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• pp.299-304
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• 2001

Xenobiotics and their reactive intermediates bind to cellular macromolecules and/or generate oxidative stress. which provoke deleterious effects on the cell function. Induction of xenobiotic-biotrans-forming enzymes and antioxidant molecules is an important defense mechanism against such insults. A group of genes involved in the defense mechanism. e.g. genes encoding glutathione S-transferases. NAD(P)H: quinone oxidoreductase, UDP-glucuronosyltransferase (UDP-GT) and ${\gamma}$-glutamylcysteine synthetase (GGCS). have a common regulatory sequence, Antioxidant or Electrophile Responsive Element (ARE/EpRE). Recently. Nrf2. discovered as a homologue of erythroid transcription factor p45 NF-E2, was shown to bind ARE/EpRE and induce the expression of these defense genes. Mice that lack Nrf2 show low basal levels of expression and/or impaired induction of these genes. which makes the animals highly sensitive to xenobiotic toxicity. Indeed. we show here that nrf2-deficient mice had a higher mortality than did the wild-type mice when exposed to acetaminophen (APAP). Detailed analyses of APAP hepatotoxicity in the nrf2 knockout mice indicate that a large amount of reactive APAP metabolites was generated in the livers due to the impaired basal expression of two detoxifying enzyme genes, UDP-GT (Ugt1a6) and GGCS. while the cytochrome P450 content was unchanged. Thus. the studies using the nrf2 knockout mice clearly demonstrate significance of the expression of Nrf2-regulated enzymes in protection against xenobiotic toxicity.

• Korean Journal of Fisheries and Aquatic Sciences
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• v.45 no.2
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• pp.97-103
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• 2012

This study compared the composition and texture of muscle and levels of detoxification and antioxidant enzymes in the livers of stocked and cultivated rockfish Sebastes schlegeli released after the primary culture stage in Tongyoung, South Korea. The crude lipid content of muscle was significantly higher ($P$<0.05) in cultivated rockfish than stocked rockfish, while the texture did not differ significantly ($P$>0.05). The condition factor (CF) and hepatosomatic index (HSI) did not differ significantly and the growth of stocked and cultivated rockfish was similar. The levels of the detoxification enzymes cytochrome P450 (CYP) and Ethoxyresorufin-O-deethylase (EROD) were significantly lower in the livers of stocked rockfish, perhaps because of their reduced exposure to xenobiotic compounds. In addition, stocked rockfish had a significantly ($P$<0.05) lower CAT and higher GR than cultivated rockfish, but similar levels of tGPx, SOD, GSH, and GSSG. The present study shows that the growth rates of stocked and cultivated rockfish are similar and that stocked rockfish are exposed to fewer xenobiotic compounds and less oxidative stress.

• Journal of Aquaculture
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• v.18 no.3
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• pp.200-206
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• 2005

We previously pointed out that the polluted sediment elutriate manifestly affected the early events of reproductive outputs in the Pacific oysters, Crassostrea gigas. A serial dilution of priority xenobiotic sediment elutriates determined by gas chromatography/mass spectrometry (GC/MS) were exposed to gametes of the oyster with different stress burdens to detail the maternal stress transfer to its reproductive outputs. There was an apparent critical concentration over which survival and morphogenesis were significantly affected with more profound damage in morphogenesis. The critical concentration which drives mortality and abnormal morphogenesis of the larvae corresponded to a dilution between 10 and 20% of our elutriate. The adverse effects of the early lives by the xenobiotic exposure over the critical concentration were magnified by the maternal stress from the exposed benzo(a)pyrene (BaP), one of the priority polyaromatic hydrocarbons (PAHs) during the maturation condition. These results indicate that maternal transfer of the xenobiotic compounds from oysters living in the contaminated location might represent a significant adverse effect to their larval population of wild seeds.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.8
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• pp.3371-3376
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• 2015

Pigmented rice bran has been suggested to be a valuable source of beneficial phytochemicals. We investigated genotoxic and anti-genotoxic effects of purple rice bran extract (PRBE) in rats using a liver micronucleus assay. Purple rice bran was extracted with methanol, obtaining large amounts of phenolic compounds, including anthocyanins and small amounts of gamma-oryzanol. The experimental protocols were divided into two sets. Male rats were divided into three groups. Group 1 was a negative control, while Groups 2 and 3 were fed with 100 and 500 mg/kg bw of PRBE, respectively, for 28 days. PRBE had no effect on micronucleus formation or xenobiotic metabolizing enzymes in rat liver. Experiments concerning the effect of PRBE on $AFB_1$ showed that PRBE significantly lessened the amount of micronucleated hepatocytes in $AFB_1$ treated rats. Furthermore, it modulated metabolic activation of $AFB_1$ metabolism in the liver by suppressing activity and protein expression of CYP1A2, CYP3A and CYP 450 reductase, and enhancing phase II enzymes including GST and UGT. Overall, purple rice bran extract was not genotoxic in rats. It exhibited anti-genotoxicity by modulation some xenobiotic enzymes active in $AFB_1$ metabolism.

• Proceedings of the Korea Environmental Mutagen Society Conference
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• 2004.05a
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• pp.27-29
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• 2004

Drug transporters play an essential role in the absorption, distribution and elimination of clinical drugs, nutrients and toxicants. The importance of the transporters is exampled by therapeutic failure in cancer chemotherapy that is mainly caused by the overexpression of multidrug resistance (MDR)-related transporters. In addition, the transporters may involve in drug-drug interactions that lead to serious adverse drug responses and some transporters also contribute to inter-individual variation in drug responses. As an effort to understand the mechanism underlying the inter-individual variation of transporters activity, genetic and environmental factors influencing the expression or function of the transporters have extensively explored through last decade. Among them, genetic polymorphism of drug transporter encoding genes has generated much interest since the discovery of functional single nucleotide polymorphisms (SNP) of MDR1 gene. Besides drug transporters, xenobiotic receptors also modulate drug disposition by regulating the transcription of drug metabolizing enzymes and drug transporters. Among many xenobiotic receptors, pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are two most well characterized since these receptors show wide substrate specificities and regulate the expression of various enzymes involved in drug disposition. Recently, several functional genetic polymorphisms were reported in PXR coding gene. In the present study, genetic polymorphisms of two drug transporters, MDR1 and BCRP, and two xenobiotic receptors, PXR and CAR, were investigated in Korean population.

• Proceedings of the Korean Society of Toxicology Conference
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• 2004.05a
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• pp.27-29
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• 2004

Drug transporters play an essential role in the absorption, distribution and elimination of clinical drugs, nutrients and toxicants. The importance of the transporters is exampled by therapeutic failure in cancer chemotherapy that is mainly caused by the overexpression of multidrug resistance (MDR)-related transporters. In addition, the transporters may involve in drug-drug interactions that lead to serious adverse drug responses and some transporters also contribute to inter-individual variation in drug responses. As an effort to understand the mechanism underlying the inter-individual variation of transporters activity, genetic and environmental factors influencing the expression or function of the transporters have extensively explored through last decade. Among them, genetic polymorphism of drug transporter encoding genes has generated much interest since the discovery of functional single nucleotide polymorphisms (SNP) of MDRl gene. Besides drug transporters, xenobiotic receptors also modulate drug disposition by regulating the transcription of drug metabolizing enzymes and drug transporters. Among many xenobiotic receptors, pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are two most well characterized since these receptors show wide substrate specificities and regulate the expression of various enzymes involved in drug disposition. Recently, several functional genetic polymorphisms were reported in PXR coding gene. In the present study, genetic polymorph isms of two drug transporters, MDR1 and BCRP, and two xenobiotic receptors, PXR and CAR, were investigated in Korean population.

• Journal of Life Science
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• v.34 no.3
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• pp.199-207
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• 2024

Cytochrome P450s (CYP) enzymes play a central role in the metabolism of both endogenous and xenobiotic chemical compounds. In particular, therapeutic drugs, natural products and environmental toxicants regulate expression of the tissue-specific CYP enzymes, This can cause CYP-mediated interactions among the chemical compounds such as the ingested drugs and toxicants, resulting in changes in their metabolism. This can lead to the modifications of their therapeutic and toxic effects. Intense investigations in this field throughout the last several decades have resulted in considerable progress in understanding the molecular mechanisms mediating the regulation of CYP gene expression. Now, it is well established that xenobiotic chemicals regulate the expression of specific CYP genes, and the corresponding xenobiotic-sensing receptors that mediate the expression control of specific CYP genes and their signal transduction pathways are involved in this process. This review summarizes the molecular mechanisms by which the well-known major xenobiotic-sensing receptors and other regulators affect the induction of CYP gene expression in response to exposure to various chemicals.