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Scientists from Canadian institutions have a rich history of making interesting and important contributions to the journal (DMD) over the past 51 years. A goal of this minireview is to highlight these contributions and pay tribute to many of the scientists at Canadian institutions that have aided in the evolution of the discipline through their DMD publications. We conducted a geographical and research sectoral analysis of the temporal trends of DMD publications originating from Canadian sources.

Fifty Years of Aryl Hydrocarbon Receptor Research as Reflected in the Pages of .

The induction of multiple drug-metabolizing enzymes by halogenated and polycyclic aromatic hydrocarbon toxicants is mediated by the aryl hydrocarbon receptor (AHR). This fascinating receptor also has natural dietary and endogenous ligands, and much is now appreciated about the AHR's developmental and physiologic roles, as well as its importance in cancer and other diseases. The past several years has witnessed increasing emphasis on understanding the multifaceted roles of the AHR in the immune system.

Mechanisms of NADPH - cytochrome P450 oxidoreductase induction by dexamethasone in the H4IIE rat hepatoma cell line.

Expression of NADPH - cytochrome P450 oxidoreductase (POR), electron donor for microsomal P450s, is induced in rat liver by dexamethasone (DEX), an activator of the glucocorticoid receptor (GR) and the pregnane X receptor (PXR). DEX induction of POR in rat liver is primarily PXR-mediated, although GR may contribute to mRNA effects. We examined the role of GR and PXR in the DEX induction of POR mRNA and protein in the H4IIE rat hepatoma cell line.

Suppression of Hepatic Expression and Activity by 3-Methylcholanthrene in Humanized PXR-CAR-CYP3A4/3A7 Mice.

Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants that activate the aryl hydrocarbon receptor, thereby triggering a range of biologic responses, exemplified by the induction of PAHs can also regulate the expression of members of the subfamily, with reports of mainly suppressive effects on mouse hepatic expression, but paradoxically both inductive and suppressive effects on human hepatic expression. Understanding the regulation of expression by PAHs is important because of the widespread exposure of humans to these chemicals and the central role of the CYP3A4 enzyme in the metabolism of clinically important drugs and endogenous substances. The present study used 3-methylcholanthrene (MC) as a model PAH to characterize the in vivo regulation of expression and activity in humanized pregnane X receptor-constitutive androstane receptor-CYP3A4/3A7 mice.

Downregulation of cytochrome P450 2C8 by 3-methylcholanthrene in human hepatocellular carcinoma cell lines.

The marked induction of cytochromes P450 such as CYP1A1 caused by polycyclic aromatic hydrocarbons (PAHs) like 3-methylcholanthrene (MC) is often accompanied by suppression of other hepatic P450s. The molecular mechanisms, functional consequences, and human relevance of P450 downregulation by PAHs are poorly understood. MC suppresses mRNA levels for CYP2C8, an important human P450, in cultured human hepatocytes.

Biofuel blending reduces particle emissions from aircraft engines at cruise conditions.

Aviation-related aerosol emissions contribute to the formation of contrail cirrus clouds that can alter upper tropospheric radiation and water budgets, and therefore climate. The magnitude of air-traffic-related aerosol-cloud interactions and the ways in which these interactions might change in the future remain uncertain. Modelling studies of the present and future effects of aviation on climate require detailed information about the number of aerosol particles emitted per kilogram of fuel burned and the microphysical properties of those aerosols that are relevant for cloud formation.

Role of Glucocorticoid Receptor and Pregnane X Receptor in Dexamethasone Induction of Rat Hepatic Aryl Hydrocarbon Receptor Nuclear Translocator and NADPH-Cytochrome P450 Oxidoreductase.

The aryl hydrocarbon receptor (AHR) nuclear translocator (ARNT), as the AHR's heterodimerization partner, and NADPH-cytochrome P450 oxidoreductase (POR), as the key electron donor for all microsomal P450s, are independent and indispensable components in the adaptive and toxic responses to polycyclic aromatic hydrocarbons. Expression of both ARNT and POR in rat liver is induced by dexamethasone (DEX), a synthetic glucocorticoid known to activate both the glucocorticoid receptor (GR) and the pregnane X receptor (PXR). To better understand the role of GR and PXR in the in vivo DEX induction of rat hepatic ARNT and POR at the mRNA and protein levels, we studied the following: 1) the effects of DEX doses that activate GR (≥0.

Loss of hepatic aryl hydrocarbon receptor protein in adrenalectomized rats does not involve altered levels of the receptor's cytoplasmic chaperones.

The aryl hydrocarbon receptor (AHR) plays physiological roles and mediates adaptive and toxic responses to environmental pollutants. Adrenalectomized rats display decreased hepatic AHR protein levels, with no change in mRNA, and selectively impaired induction of cytochrome P450 1B1. This is similar to reported phenotypes for mice with hepatocyte-specific conditional deletion of AHR-interacting protein (AIP), a chaperone protein of the cytoplasmic AHR complex.

Downregulation of mouse hepatic CYP3A protein by 3-methylcholanthrene does not require cytochrome P450-dependent metabolism.

The aryl hydrocarbon receptor (AHR)-dependent induction of cytochromes P450 (P450) such as CYP1A1 by 3-methylcholanthrene (MC) and related polycyclic aromatic hydrocarbons is well characterized. We reported previously that MC treatment triggers a pronounced downregulation, particularly at the protein level, of mouse hepatic Cyp3a11, a counterpart of the key human drug-metabolizing enzyme CYP3A4. To determine whether this effect of MC requires hepatic microsomal P450 activity, we studied liver Cpr-null (LCN) mice with hepatocyte-specific conditional deletion of the NADPH-cytochrome P450 oxidoreductase gene.

The role of cytochrome P450-dependent metabolism in the regulation of mouse hepatic growth hormone signaling components and target genes by 3-methylcholanthrene.

3-Methylcholanthrene (MC) is a readily metabolized aryl hydrocarbon receptor (AHR) agonist. MC disrupts expression of mouse hepatic growth hormone (GH) signaling components and suppresses cytochrome P450 2D9 (Cyp2d9), a male-specific gene controlled by pulsatile GH via signal transducer and activator of transcription 5b (STAT5b). To determine if these effects of MC depend on hepatic microsomal P450-mediated activity, we examined biologic responses to MC treatment in liver Cpr-null (LCN) mice with hepatocyte-specific conditional deletion of NADPH-cytochrome P450 oxidoreductase (POR).

Induction of multidrug resistance transporter ABCG2 by prolactin in human breast cancer cells.

The multidrug transporter, breast cancer resistance protein, ABCG2, is up-regulated in certain chemoresistant cancer cells and in the mammary gland during lactation. We investigated the role of the lactogenic hormone prolactin (PRL) in the regulation of ABCG2. PRL dose-dependently induced ABCG2 expression in T-47D human breast cancer cells.

NADPH-cytochrome P450 oxidoreductase: roles in physiology, pharmacology, and toxicology.

This is a report on a symposium sponsored by the American Society for Pharmacology and Experimental Therapeutics and held at the Experimental Biology 2012 meeting in San Diego, California, on April 25, 2012. The symposium speakers summarized and critically evaluated our current understanding of the physiologic, pharmacological, and toxicological roles of NADPH-cytochrome P450 oxidoreductase (POR), a flavoprotein involved in electron transfer to microsomal cytochromes P450 (P450), cytochrome b(5), squalene mono-oxygenase, and heme oxygenase. Considerable insight has been derived from the development and characterization of mouse models with conditional Por deletion in particular tissues or partial suppression of POR expression in all tissues.

Aryl hydrocarbon receptor-dependence of dioxin's effects on constitutive mouse hepatic cytochromes P450 and growth hormone signaling components.

The aryl hydrocarbon receptor (AHR) has physiological roles in the absence of exposure to exogenous ligands, and mediates adaptive and toxic responses to the environmental pollutant 2,3,7,8-tetracholorodibenzo-p-dioxin (TCDD). A readily metabolized AHR agonist, 3-methylcholanthrene, disrupts the expression of mouse hepatic growth hormone (GH) signaling components and suppresses cytochrome P450 2D9 (Cyp2d9), a male-specific gene controlled by pulsatile GH via signal transducer and activator of transcription 5b (STAT5b). Using TCDD as an essentially nonmetabolized AHR agonist, and Ahr (-/-) mice as the preferred model to determine the AHR-dependence of biological responses, we now show that 2 mouse hepatic STAT5b target genes, Cyp2d9, and major urinary protein 2 (Mup2), are suppressed by TCDD in an AHR-dependent manner.

The aryl hydrocarbon receptor pathway and the response to 3-methylcholanthrene are altered in the liver of adrenalectomized rats.

The aryl hydrocarbon receptor (AHR) is activated by 3-methylcholanthrene (MC), a polycyclic aromatic hydrocarbon, and environmental contaminants, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin. Adrenalectomized (ADX) rats have decreased hepatic AHR protein and lower levels of MC-induced CYP1B1 mRNA. To further characterize the effects of decreased AHR protein and the response to MC in ADX rats, we measured AHR-mediated responses in the liver of sham-operated (SHAM) and ADX rats, 6 and 54 h after MC treatment.

Glucocorticoid and adrenalectomy effects on the rat aryl hydrocarbon receptor pathway depend on the dosing regimen and post-surgical time.

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the effects of aromatic hydrocarbons, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin and 3-methylcholanthrene (MC); the prototypical response is induction of drug-metabolizing enzymes. Factors that regulate AHR levels in vivo are poorly understood and it is also not clear how AHR levels affect aromatic hydrocarbon responsiveness. Our interest in pituitary-dependent regulation of AHR levels was prompted by two findings from our laboratory: (1) hypophysectomized rats have reduced hepatic levels of AHR protein; and (2) glucocorticoids increase AHR expression and aromatic hydrocarbon responsiveness in rodent hepatoma cells.

Cytochrome P450 2C11 5'-flanking region and promoter mediate in vivo suppression by 3-methylcholanthrene.

Aromatic hydrocarbons such as 3-methylcholanthrene (MC) elicit toxic and adaptive responses through the aryl hydrocarbon receptor (AHR). Aromatic hydrocarbons act via an unknown mechanism to suppress the transcription of CYP2C11, a growth hormone-regulated gene encoding the male-specific rat hepatic cytochrome P450 2C11. We hypothesize that suppression of CYP2C11 by aromatic hydrocarbons is mediated by the gene's promoter and 5'-flank.

Cytochrome P450 2C11 5'-flanking region and promoter: regulation by aromatic hydrocarbons in vitro.

Aromatic hydrocarbons elicit toxic and adaptive responses via the aryl hydrocarbon receptor (AHR). Aromatic hydrocarbons suppress the transcription of the growth hormone-regulated, male-specific rat hepatic cytochrome P450 2C11 gene (CYP2C11) in vivo via an unknown mechanism. We hypothesize that the suppression of CYP2C11 by aromatic hydrocarbons is mediated by the gene's promoter and 5'-flanking region.

Regulation of aryl hydrocarbon receptor expression and function by glucocorticoids in mouse hepatoma cells.

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates most biological responses to 2,3, 7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related aromatic hydrocarbons. Although the role of the AHR in control of drug metabolism and endocrine disruption is partly understood, we know little about the regulation of the AHR itself by endocrine factors. Our work with hypophysectomized rats suggested that hepatic AHR protein level is positively regulated by pituitary-dependent factors.

Regulation of constitutive mouse hepatic cytochromes P450 and growth hormone signaling components by 3-methylcholanthrene.

3-Methylcholanthrene (MC) activates the aryl hydrocarbon receptor and increases expression of cytochrome P450 (P450) enzymes such as CYP1A1. MC also decreases expression of CYP2C11, the major hepatic P450 in male rats that is regulated by pulsatile growth hormone (GH) secretion via a pathway partially dependent on signal transducer and activator of transcription 5b (STAT5b). If disruption of this GH signaling pathway is important for MC's ability to suppress CYP2C11 transcription, we hypothesize that MC suppresses other male-specific genes (e.

Regulating the regulator: factors that control levels and activity of the aryl hydrocarbon receptor.

The aryl hydrocarbon receptor (AHR) participates in a wide range of critical cellular events in response to endogenous signals or xenobiotic chemicals. Hence, it is important that AHR levels and activity themselves be well controlled in target tissues. The AHR is essentially ubiquitous in its distribution in mammalian tissues.

Cancer chemotherapy and drug metabolism.

Drug-metabolizing enzymes and drug transporters are key determinants of the pharmacokinetics and pharmacodynamics of many antineoplastic agents. Metabolism and transport influence the cytotoxic effects of antineoplastic agents in target tumor cells and normal host tissues. This article summarizes several state-of-the-art approaches to enhancing the effectiveness and safety of cancer therapy based on recent developments in our understanding of antineoplastic drug metabolism and transport.

Transcriptional suppression of cytochrome P450 genes by endogenous and exogenous chemicals.

This article is an invited report of a symposium sponsored by the Division for Drug Metabolism of the American Society for Pharmacology and Experimental Therapeutics held at Experimental Biology 2003 in San Diego, California, April 11-15, 2003. Several members of the cytochrome P450 (P450) superfamily are induced after exposure to a variety of chemical signals, and we have gained considerable mechanistic insight into these processes over the past four decades. In addition, the expression of many P450s is suppressed in response to various endogenous and exogenous chemicals; however, relatively little is known about the molecular mechanisms involved.

Human NADPH-cytochrome p450 reductase overexpression does not enhance the aerobic cytotoxicity of doxorubicin in human breast cancer cell lines.

Doxorubicin is a useful antineoplastic drug with multiple mechanisms of cytotoxicity. One such mechanism involves the reductive bioactivation of the quinone ring to a semiquinone radical, which can exert direct toxic effects and/or undergo redox cycling. We hypothesized that human NADPH-cytochrome p450 reductase (CYPRED) catalyzes doxorubicin reduction and that overexpression of this enzyme sensitizes human breast cancer cell lines to the aerobic cytotoxicity of doxorubicin.

The 2001 Veylien Henderson Award of the Society of Toxicology of Canada. Positive and negative transcriptional regulation of cytochromes P450 by polycyclic aromatic hydrocarbons.

Most responses to aromatic hydrocarbons such as 3-methylcholanthrene (MC) and 2,3,7,8-tetrachlorodibenzo-p-dioxin are mediated by the aromatic hydrocarbon receptor (AHR). The AHR regulates induction of drug-metabolizing enzymes such as cytochrome P450 1A1. However, the expression of several genes of biological significance is decreased by these chemicals.

Aromatic hydrocarbon receptor expression and function in liver of hypophysectomized male rats.

The aromatic hydrocarbon receptor (AHR) acts as a ligand-activated transcription factor that mediates many of the biological responses to aromatic hydrocarbons, such as 3-methylcholanthrene (MC) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Some toxic effects are thought to be the result of AHR-mediated changes in the expression of endocrine-related genes, such as the estrogen receptor and genes involved in cell growth and differentiation. Since little is known about endocrine factors that regulate AHR expression and function, we evaluated the effect of hypophysectomy (hypx) on these parameters in the liver of male rats.