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Cytochrome P450-Dependent Metabolism of Drugs and Carcinogens in Skin
Published in Rhoda G. M. Wang, James B. Knaak, Howard I. Maibach, Health Risk Assessment, 2017
The pretreatment of animals with a wide range of xenobiotics, either applied topically or administered systemically, have been shown to result in significant induction of cutaneous AHH activity and other drug metabolizing enzyme activities including 7-ethoxycoumarin O-deethylase (ECD) and 7-ethoxyresorufin O-deethylase (ERD).1”8 However, the inducibility of AHH, ECD, and ERD activities in skin was significantly more after topical application of xenobiotics when compared to any other mode of exposure.33,49
2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) and Related Environmental Antiestrogens:Characterization and Mechanism of Action
Published in Rajesh K. Naz, Endocrine Disruptors, 2004
TCDD and related compounds inhibit growth of ER-independent pancreatic and prostate cancer cell lines, and in the former cells, this was associated with upregulation of p21 expression.145,146 In parallel studies, AhR expression and function has been investigated in several ER-negative breast cancer cell lines. Results illustrated in Figure 8.5 show that TCDD induces AhR-dependent ethoxyresorufin O-deethylase activity in MDA-MB-157, MDA-MB-436, MDA-MB-134, BT-20, MDA-MB-453, BT-474, MDA-MB-435, and HCC-38 cells, and in parallel studies, TCDD and related compounds also inhibited proliferation of these ER-negative breast cancer cell lines. However, the mechanisms of TCDD-induced growth inhibition are not related to modulation of p21, other cell cycle regulated genes, or kinase activities, and current studies are investigating other potential AhR-dependent pathways that influence ER-negative breast cancer cell proliferation.
Dimethylarsinic acid modulates the aryl hydrocarbon receptor-regulated genes in C57BL/6 mice: in vivo study
Published in Xenobiotica, 2018
Osama H. Elshenawy, Ghada Abdelhamid, Hassan N. Althurwi, Ayman O. S. El-Kadi
Cyp1a1-dependent 7-ethoxyresorufin O-deethylase (EROD) and Cyp1a2-dependent 7-methoxyresorufin O-demethylase (MROD) activities were assessed using 7-ethoxyresorufin and 7-methoxyresorufin, respectively, as substrates. Microsomes from liver, lung and kidney of various treatments (1 mg protein/ml) were incubated in the incubation buffer (5 mM magnesium chloride hexahydrate dissolved in 0.1 M potassium phosphate buffer, pH 7.4) with 7-ethoxyresorufin or 7-methoxyresorufin (2 μM final concentration) at 37 °C in a shaking water bath (50 rpm). A pre-equilibration period of 5 min was performed. The reaction was initiated by the addition of 1 mM NADPH. After incubation at 37 °C (5 min for EROD and 10 min for MROD assay), the reaction was stopped by adding 0.5 ml of cold methanol. The amount of resorufin formed in the resulting supernatant was measured using Bio-Tek Synergy H1 Hybrid Multi-Mode Microplate Readers (Bio-Tek Instruments, Winooski, VT) using excitation and emission wavelengths of 535 and 585 nm, respectively. Formation of resorufin was linear with incubation time and protein amount. Enzymatic activities were expressed as picomoles of resorufin formed per minute and per milligram of microsomal proteins.
Biotransformation enzyme activities and phase I metabolites analysis in Litopenaeus vannamei following intramuscular administration of T-2 toxin
Published in Drug and Chemical Toxicology, 2018
Yijia Deng, Yaling Wang, Lijun Sun, Pengli Lu, Rundong Wang, Lin Ye, Defeng Xu, Riying Ye, Ying Liu, Siyuan Bi, Ravi Gooneratne
At present, many T-2 studies in aquatic animals, the endpoints measured have mostly focused on metabolite analysis and immunotoxicity (Chatterjee et al.1986, Yoshizawa et al.1982, Kravchenko et al.2001, Yuan et al.2013), with only a few studies looking at the time-dependent activity of detoxification enzymes. For T-2 metabolism, it has been established that once T-2 enters the organism's system, and it will experience a series of oxidative processes mediated by the phase I and II biotransformation system. 7-Ethoxyresorufin O-deethylase (EROD) and carboxylesterase (CarE) are the important enzymes in phase I metabolism (Fonnum et al.1985, Izzo and Ernst 2009). A marked induction in EROD activity in the hepatopancreas was observed following exposure of shrimp (Xiphopenaeus kroyeri) to benzo[a]pyrene (BaP) (Da Silva et al.2012). CarE can hydrolyze T-2 at the C-4 position to HT-2, a major T-2 metabolite (Johnsen et al.1988). Therefore, it is important to assess both CarE enzyme activity and EROD in order to fully understand their roles in phase I T-2 metabolism. These phase I metabolites can be further detoxified by phase II enzymes, namely glutathione S transferase (GST), sulfotransferases (SULT), and uridine diphosphate glucuronosyltransferase (UGT) (Dixon et al.2000, Oost et al.2003, Chaudhary and Rao 2010). In mice, exposure to T-2 can deplete hepatic glutathione (GSH) and GST activity (Chaudhari et al.2009). Though SULT and UGT play important roles in T-2 metabolism and were frequently studied in mammals, studies involving these enzyme activities in crustaceans exposed to T-2 are limited. Therefore, it is very important to investigate detoxification metabolism of T-2 in crustaceans.
Effects of dechlorane plus on oxidative stress, inflammatory response, and cell apoptosis in Cyprinus carpio
Published in Drug and Chemical Toxicology, 2022
Baohua Li, Pengju Qi, Ying Qu, Beibei Wang, Jianjun Chen, Zhongjie Chang
CYPs detoxify exogenous chemicals such as drugs, carcinogens, and environmental pollutants (Uno et al. 2012). Numerous studies on CYPs in fish demonstrated their utility as aquatic pollution biomarkers (Fent, 2003, Moore, 2003, Williams et al., 1998). Cyp1a1-dependent ethoxyresorufin-O-deethylase (EROD) activity is an indicator of environmental contamination by polycyclic aromatic hydrocarbons (PAHs) and dioxins ( Schlezinger and Stegeman, 2001, Orrego, 2005, Parente et al., 2008). The liver is an important detoxification organ and essential for the excretion of fish poisons (Hinton and Lauren, 1990). More than 90% of all drugs and heterotoxic poisons are metabolized and detoxified by CYP molecules in the liver (Landi 2000, Nelson 2003). In the present study, cyp1b1, cyp2b4 and cyp3a138 were significantly upregulated in the livers of fish exposed to DP. Therefore, hepatic detoxification function may have been increased. At high DP concentrations, however, the expression levels of cyp1b1 and cyp3a138 were lower at 30-d exposure than they were at 15-d exposure. Thus, the activity of these enzymes may vary with stress level and duration. These results suggest that cyps may participate in hepatic DP detoxification. In the brains of carp, cyp1b1 was markedly upregulated. For this reason, cyp1b1 may be involved in cerebral detoxification processes. The cyp3a138 expression level nonsignificantly increased with DP concentration except on day 30 at high DP dose. Cyp2b4 was only slightly expressed in the brain even in response to DP exposure. Thus, hepatic cyps are the key DP detoxification genes in carp while cerebral cyps mainly protect the brain and nerves from toxicant injury.