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Transdermal estrogen therapy and the risk of breast cancer: a clinical appraisal
Published in A. R. Genazzani, Hormone Replacement Therapy and Cancer, 2020
Estrogen catabolism takes place in two stages: hydroxylation and methylation (Figure 1). Estrone and estradiol are hydroxylated to the following: 2-hydroxyestrone (2-OHE1); 2-hydroxyestradiol (2-OHE2); 4-hydroxyestrone (4-OHE1); 4-hydroxyestradiol (4-OHE2); 16-hydroxyestrone (16-OHE1); and 16-hydroxyestradiol (16-OHE2). The 2-hydroxy estrogens are referred to as the A-ring metabolites, and 16-hydroxy estrogens as the D-ring metabolites. The D-ring metabolites are bioavailable and estrogenic. Women who preferentially metabolize their endogenous estrogens via the 16a-hydroxylation pathway (versus 2α-hydroxylation) are at higher risk of breast cancer9. The hydroxylation of estrogen is genetically controlled; for example, the CYP1A1 gene, which encodes cytochrome p450 1A1, inhibits or downgrades the activity of the 2<x-hydroxy pathway, thereby diminishing the concentration of the benign protective 2-hydroxy estrogens in favor of the biologically potent 16-hydroxyestradiol metabolite10.
Amiodarone pulmonary toxicity
Published in Philippe Camus, Edward C Rosenow, Drug-induced and Iatrogenic Respiratory Disease, 2010
Philippe Camus, Thomas V Colby, Edward C Rosenow
Amiodarone is chiefly metabolized in the liver into its chief metabolite mono-desethylamiodarone (usually refered to as ‘desethylamiodarone’), under cytochrome P450–1A1- and 3A4-driven dealkylation. Desethylamiodarone plasma concentration is 30–120 per cent that of amiodarone,14 and it may be more in amiodarone toxic patients. Desethylamiodarone participates in the antiarrhythmic efficacy of amiodarone, and is also capable of producing phospholipidosis. Further dealkylation of desethylamiodarone leads to minute amounts of bis-desethylamiodarone. Metabolism of amiodarone takes place to a lesser extent in the gut. There is insignificant biotransformation of amiodarone in the lungs. Upon metabolism, amiodarone and its metabolite are excreted into the bile and eliminated via the faecal route. Although desethylamiodarone is more water-soluble and more readily excretable than is amiodarone, it sequesters about 5-fold more in tissues compared to amiodarone, particularly in liver and lung. Further, desethylamiodarone is more toxic to lung cells than is amiodarone, with a LD50 2.5-to 18-fold less than that for amiodarone. Thus, desethylamiodarone may play a pathogenic role in APT. There is no significant correlation of amiodarone or desethylamiodarone concentration in plasma and the likelihood of developing pulmonary toxicity. Likewise, plasma concentration of amiodarone and/or desethylamiodarone or their ratio may not reliably separate amiodarone-toxic from non-toxic patients in clinical practice.
Use of Biomarkers in Occupational Safety and Health
Published in Anthony P. DeCaprio, Toxicologic Biomarkers, 2006
PAH absorption and uptake has been monitored by several different biomarkers, including urinary metabolites, protein adducts, and DNA adducts. Urinary mutagenicity and urinary thioethers have also been used in studies of workers but, because they are nonspecific indicators of PAH exposure and subject to confounding exposures, they are not suitable for routine biomonitoring (47). The most widely used biomarker of human exposure to PAH is the measurement of urinary 1-hydroxypyrene (1-OHP), a metabolite of pyrene (49). Pyrene is relatively abundant in PAH mixtures and metabolized and excreted as a glucuronide in urine. Half-lives for urinary formation of 1-OHP are relatively long, ranging from 6 to 48 hours, allowing for the collection of spot urine samples at the end of a work shift and end of a work week (47). Other data suggest that a sampling strategy where urine is collected over a 24-hour period gives a better estimate of the relationship between PAH dose and 1-OHP metabolite levels (50,51). In general, published occupational health studies using the urinary 1-OHP marker have used the spot sample protocol and include workers in asphalt paving (52), aluminum smelting (53), coke oven refineries (54), coal tar painting (55), and steel manufacturing (56). In each of these studies, urinary 1-OHP was demonstrated as a useful measure of recent PAH exposure, which had occurred by multiple routes. These studies also demonstrate, however, that cigarette smoking, diet, nonoccupational environmental exposures, and genetic polymorphisms of cytochrome P450 1A1 and glutathione transferases can all affect urinary concentration of 1-OHP.
Effects of pyrethroids on the cerebellum and related mechanisms: a narrative review
Published in Critical Reviews in Toxicology, 2023
Fei Hao, Ye Bu, Shasha Huang, Wanqi Li, Huiwen Feng, Yuan Wang
Some individuals believe that specific induction of cytochrome P450 by PYRs may significantly impact local regulatory mechanisms pertaining to enzymatic activity, thereby influencing drug response and increasing the risk of neurotoxicity (Vences-Mejía et al. 2012). According to a study, the variations in the induction of individual cytochrome P450 isoenzymes across diverse brain regions may modulate their concentrations or active metabolites at the target sites. These cytochrome P450 isoenzymes are involved in the regulation of brain response to PYRs (Dayal et al. 2001). This study has demonstrated that oral administration of DM leads to an increase in the activity of cytochrome P450-dependent 7-ethoxyresorufin-O-deethylase (EROD) and 7-pentoxyresorufin-O-dealkylase (PROD) in rat brain microsomes. The cerebellum exhibited a significant induction of cytochrome P450 1A1/2-dependent EROD activity. Yadav et al. (Yadav et al. 2006) further found that cytochrome P450 1A1, cytochrome P450 1A2, cytochrome P450 2B1 and cytochrome P450 2B2 mRNA expression were also significantly increased in the cerebellum. Later experimental results also supported the above findings (Vences-Mejía et al. 2012). Elevated cytochrome P450 2E1 levels in the CNS may increase the risk of neurotoxicity caused by oxidative stress, which is an underlying factor in blood-brain barrier damage, neuroinflammation and neurodegeneration (Cederbaum et al. 2001; Tiwari et al. 2010).
The interplay between aryl hydrocarbon receptor, H. pylori, tryptophan, and arginine in the pathogenesis of gastric cancer
Published in International Reviews of Immunology, 2022
Marzieh Pirzadeh, Nastaran Khalili, Nima Rezaei
When there is no ligand to bind to AHR, this receptor forms a complex with two chaperone heat shock protein 90 (HSP90), a small protein named p23, and an immunophilin-like protein known as XAP2 in the cell cytosol. However, upon binding to its ligands, these proteins dissever and AHR translocates to the nucleus and binds to AHR nuclear translocator and forms a heterodimer. This heterodimer attaches to a special part of the DNA named dioxin response element (DRE), and then AHR controls and regulates the expression of a varied set of genes [60]. Some of the important genes that AHR controls are genes that code for xenobiotic metabolizing enzymes such as cytochrome P450 1A1 (CPY1A1), cytochrome P450 1B1 (CPY1B1) and glutathione-S-transferase which detoxify and metabolize drugs and xenobiotics entering the human body [61–63].
Dietary natural flavonoids treating cancer by targeting aryl hydrocarbon receptor
Published in Critical Reviews in Toxicology, 2019
Tian Yang, Ya-Long Feng, Lin Chen, Nosratola D. Vaziri, Ying-Yong Zhao
The AhR is a member of the basic helix-loop-helix-PER-ARNT-SIM (bHLH-PAS) subgroup of the bHLH superfamily of transcription factors and is the only member of this family known to be activated by ligands (Figure 1). The unliganded AhR resides in the cytoplasm of a cell, forming a complex with a heat shock protein 90 (HSP90) dimer and the co-chaperone protein X-associated protein 2 (XAP2). After binding an agonist, the AhR complex translocates to the nucleus and AhR nuclear translocator (ARNT) mediates HSP90 displacement, leading to AhR-ARNT heterodimer formation. This heterodimer is capable of binding to a dioxin-responsive element (DRE) and both AhR and ARNT can recruit co-activators, leading to the transcription of a wide variety of genes. The AhR target gene cytochrome P450 1A1 (CYP1A1) is almost totally dependent on AhR activity for expression and is highly induced by AhR activation through multiple DREs (Murray et al. 2014). CYP1A1 metabolizes a number of pro-carcinogens, such as BaP, to intermediates that can react with DNA to form adducts, resulting in mutagenesis and cancer (Zapletal et al. 2017). In view of the significant role of AhR in human physiology and pathophysiology, agonists or antagonists of AhR have the potential to become new targeted therapeutic agents for cancer.