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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.
Development and validation of probe drug cocktails for the characterization of CYP450-mediated metabolism by human heart microsomes
Published in Xenobiotica, 2019
Jade Huguet, Fleur Gaudette, Veronique Michaud, Jacques Turgeon
Bufuralol 1-hydroxylation maximal velocity was decreased 2.3-times compared to a 3.6-times decrease in its apparent Km when incubated in cocktail #2 versus alone (Table 5, Figure 2(A)). Bufuralol 1-hydroxylation CLint was increased 1.7-time when incubated in cocktail #2 (Table 5). Ethoxyresorufin O-deethylase (EROD) activity with rhCYP1A1 was unchanged by the presence of other substrates in cocktail #2 (Figure 2(B)). Repaglinide hydroxylation on the piperidine ring through rhCYP2C8 fitted a substrate inhibition model (Figure 2(C), Table 5) when the drug was incubated as part of cocktail #2. Ratios of kinetic parameters derived from a substrate inhibition model from incubations performed with either cocktail #2 or alone were close to unity for Km (Km cocktail#2/Km solo = 0.9, p > .05) and Vmax (Vmax cocktail#2/Vmax solo = 1.06, p > .05). Repaglinide maximal velocity of its M1 metabolite formation with rhCYP2C8 was increased 4.56-times when incubations were performed with cocktail #2 while its apparent Km was decreased by 2.82-times (p < .05, Figure 2(D) and Table 5). Repaglinide clearance through M1-formation pathway represents 2% of the hydroxylated-pathway when incubated alone with rhCYP2C8 and remains at 2% when co-incubated in cocktail #2.
Co-treatment with indole-3-carbinol and resveratrol modify porcine CYP1A and CYP3A activities and expression
Published in Xenobiotica, 2018
Galia Zamaratskaia, Rebekka Thøgersen, Marjeta Čandek-Potokar, Martin Krøyer Rasmussen
CYP1A activity was determined as the rate of ethoxyresorufin-O-deethylase (EROD) using 7-ethoxyresorufin as a substrate, while CYP3A activity was determined as the rate of 7-benzyloxy-4-trifluoromethylcoumarin-O-debenzylation (BFC) using 7-benzyloxy-4-trifluoromethylcoumarin as substrate. The incubation times (5 min for both CYP1A and CYP3A) were chosen based on previous experiments (Ekstrand et al., 2015) and were in the linear range for the rate of metabolite formation. All measurements were performed in duplicates. I3C and RES (concentrations from 0.44 to 44 μM) were dissolved in methanol and added to the incubation tubes. After evaporation of methanol to dryness, the studied compounds were reconstituted in incubation medium containing 50 mM phosphate buffer (pH 7.4) together with 0.2 mg of microsomal protein and substrate. The reaction was started by the addition of 0.5 mM NADPH and terminated by adding 0.5 mL of ice-cold methanol.
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.