Arthur K. Cho

Nrf2 Is a Key Transcription Factor That Regulates Antioxidant Defense in Macrophages and Epithelial Cells: Protecting against the Proinflammatory and Oxidizing Effects of Diesel Exhaust Chemicals

The proinflammatory effects of particulate pollutants, including diesel exhaust particles (DEP), are related to their content of redox cycling chemicals and their ability to generate oxidative stress in the respiratory tract. An antioxidant defense pathway, which involves phase II enzyme expression, protects against the pro-oxidative and proinflammatory effects of DEP. The expression of enzymes, including heme oxygenase-1 (HO-1) and GST, is dependent on the activity of a genetic antioxidant response element in their promoters. In this study we investigated the mechanism by which redox cycling organic chemicals, prepared from DEP, induce phase II enzyme expression as a protective response. We demonstrate that aromatic and polar DEP fractions, which are enriched in polycyclic aromatic hydrocarbons and quinones, respectively, induce the expression of HO-1, GST, and other phase II enzymes in macrophages and epithelial cells. We show that HO-1 expression is mediated through accumulation of the bZIP transcription factor, Nrf2, in the nucleus, and that Nrf2 gene targeting significantly weakens this response. Nrf2 accumulation and subsequent activation of the antioxidant response element is regulated by the proteasomal degradation of Nrf2. This pathway is sensitive to pro-oxidative and electrophilic DEP chemicals and is also activated by ambient ultrafine particles. We propose that Nrf2-mediated phase II enzyme expression protects against the proinflammatory effects of particulate pollutants in the setting of allergic inflammation and asthma.

Evaluating the Toxicity of Airborne Particulate Matter and Nanoparticles by Measuring Oxidative Stress Potential—A Workshop Report and Consensus Statement

Background: There is a strong need for laboratory in vitro test systems for the toxicity of airborne particulate matter and nanoparticles. The measurement of oxidative stress potential offers a promising way forward. Objectives:Aworkshop was convened involving leading workers from the field in order to review the available test methods and to generate a Consensus Statement. Discussions: Workshop participants summarised their own research activities as well as discussion the relative merits of different test methods. Conclusions: In vitro test methods have an important role to play in the screening of toxicity in airborne particulate matter and nanoparticles. In vitro cell challenges were preferable to in vitro acellular systems but both have a potential major role to play and offer large cost advantages relative to human or animal inhalation studies and animal in vivo installation experiments. There remains a need to compare tests one with another on standardised samples and also to establish a correlation with the results of population-based epidemiology.

Comparison of the behavioral and biochemical effects of the NMDA receptor antagonists, MK-801 and phencyclidine.

The behavioral and biochemical effects of the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801 [+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate) were compared with those of phencyclidine (PCP). In the dose range used in this study, MK-801 (0.125-0.5 mg/kg i.p.) produced ataxia and other behavioral responses which were similar to PCP (5-10 mg/kg i.p.). However, turning and backpedalling induced by MK-801 were not dose-dependent and less intense at the dose producing approximately the same level of ataxia as PCP. Neurochemically, MK-801 (0.5 mg/kg i.p.) increased dopamine turnover in the cortex and striatum, but had no effect on 5-HT systems. It was also 3.4 times less potent in inhibiting 5-HT uptake than PCP. These results suggest that the behavioral responses induced by MK-801 involve primarily the PCP receptor and the dopamine system, and that the differences from PCP reflect a reduced effect on the 5-HT neuronal system.

Ice: a new dosage form of an old drug.

Ice, which has been described as the drug of the 1990s, is a pure form of (+)methamphetamine hydrochloride; it is more dangerous because of its purity and because it can be inhaled. Taken by this route, the drug causes an effect similar to that from an intravenous dose, and much more intense than that from ingestion. The detailed mechanism of action differs from that of cocaine, but the overall stimulant effect of methamphetamine is similar. Methamphetamine effects, however, persist for hours, whereas cocaine effects are over in minutes. Ice is, therefore, just another agent for abuse by those seeking psychostimulation and, as with cocaine, compulsive abusers of amphetamines consume the drug repeatedly and continuously. Unlike cocaine, methamphetamine is a synthetic compound and is manufactured in illicit laboratories within the United States.

Determination of Four Quinones in Diesel Exhaust Particles, SRM 1649a, and Atmospheric PM2.5 Special Issue of Aerosol Science and Technology on Findings from the Fine Particulate Matter Supersites Program

Quinones are reactive organic compounds and are known to initiate reactions associated with many toxicological events. Their presence in air pollution has been demonstrated, but routine quantitative measurements are lacking. A quantitative method for the determination of four quinones was developed using diesel exhaust particles (DEP) and National Institute of Standards and Technology (NIST) Standard Reference Material (SRM) 1649a. The method was then used to analyze ambient air samples from different sites in Southern California. After extraction in dichloromethane, the target compounds were converted to their stable diacetyl derivatives and determined by electron impact GC-MS using selected ion monitoring. Calibration plots were obtained with deuterium-labeled internal standards. The four quinones, 1,2-naphthoquinone (1,2-NQ), 1,4-naphthoquinone (1,4-NQ), 9,10-phenanthraquinone (9,10-PQ), and 9,10-anthraquinone (9,10-AQ), were quantified in DEP, in SRM 1649a, and in ambient air samples of PM2.5 collected in several rural and urban sampling locations upwind and downwind of major emission sources in Central Los Angeles. Mean concentration of individual target quinones ranged from 7.9–40.4 μg/g in the DEP, and from 5–730 pg/m3 in the PM2.5 samples. Precision (repeatability and reproducibility) varied from 2–22%. Further measurements of these species in future air samples should be considered in light of their potential health significance.

Relationship between redox activity and chemical speciation of size-fractionated particulate matter

BackgroundAlthough the mechanisms of airborne particulate matter (PM) related health effects remain incompletely understood, one emerging hypothesis is that these adverse effects derive from oxidative stress, initiated by the formation of reactive oxygen species (ROS) within affected cells. Typically, ROS are formed in cells through the reduction of oxygen by biological reducing agents, with the catalytic assistance of electron transfer enzymes and redox active chemical species such as redox active organic chemicals and metals. The purpose of this study was to relate the electron transfer ability, or redox activity, of the PM samples to their content in polycyclic aromatic hydrocarbons and various inorganic species. The redox activity of the samples has been shown to correlate with the induction of the stress protein, hemeoxygenase-1.ResultsSize-fractionated (i.e. < 0.15; < 2.5 and 2.5 – 10 μm in diameter) ambient PM samples were collected from four different locations in the period from June 2003 to July 2005, and were chemically analyzed for elemental and organic carbon, ions, elements and trace metals and polycyclic aromatic hydrocarbons. The redox activity of the samples was evaluated by means of the dithiothreitol activity assay and was related to their chemical speciation by means of correlation analysis. Our analysis indicated a higher redox activity on a per PM mass basis for ultrafine (< 0.15 μm) particles compared to those of larger sizes. The PM redox activity was highly correlated with the organic carbon (OC) content of PM as well as the mass fractions of species such as polycyclic aromatic hydrocarbons (PAH), and selected metals.ConclusionThe results of this work demonstrate the utility of the dithiothreitol assay for quantitatively assessing the redox potential of airborne particulate matter from a wide range of sources. Studies to characterize the redox activity of PM from various sources throughout the Los Angeles basin are currently underway.

Disposition of methylenedioxymethamphetamine and three metabolites in the brains of different rat strains and their possible roles in acute serotonin depletion

3,4-Methylenedioxymethamphetamine (MDMA) affects both dopamine and serotonin (5-HT) systems. One of its acute actions is to cause a reversible fall in steady-state brain 5-HT concentrations. To investigate the chemical basis of this acute effect, the brain levels of the parent compound and three major metabolites, 3,4- 3,4-methylenedioxyamphetamine (MDA), 3,4-dihydroxymethamphetamine (DHMA) and 6-hydroxy-3,4-methylenedioxymethamphetamine (6-OHMDMA), were monitored, together with 5-HT levels, over a period of 6 hr in male Sprague-Dawley (SD) rats. The temporal relationships between drug concentrations of both stereoisomers and depletions were evaluated first. There was no correlation between the concentrations of the compounds measured and the extent of 5-HT depletion. Brain levels of MDMA and MDA were higher than plasma levels and exhibited a stereoselectivity in that (-)-MDMA and (+)-MDA levels were higher than those of enantiomers. The relationship between the dose of ((+)-MDMA and reduction in 5-HT levels was next investigated in SD male, SD female, and Dark Agouti (DA) female rats. These animals exhibit different capabilities of MDMA metabolism. There is a lower level of MDA, the N-demethylated metabolite of MDMA, in female SD rats than in males. Female DA rats are deficient in CYP2D isozymes, one of the enzymes responsible for demethylenation of MDMA to DHMA at pharmacological concentrations of substrate. there was a significant accuulation of MDMA in the brain and plasma of DA rats, but their 5-HT depletion was somewhat attenuated. The results indicated that MDMA ++ was apparently not the single, causative agent for the acute 5-HT depletion, which may also involve a metabolite formed by CYP2D.

Relevance of pharmacokinetic parameters in animal models of methamphetamine abuse

Although the behavioral consequences of methamphetamine (METH) abuse have been extensively documented, a more precise and thorough understanding of underlying neurobiological mechanisms still requires the use of animal models. To study these biochemical processes in experimental animals requires consideration for the broad range of human METH abuse patterns and the many factors that have been identified to profoundly influence the behavioral and neurochemical effects of exposure to METH‐like stimulants. One potentially critical issue relates to pharmacokinetic differences between the species. In this review, METH plasma pharmacokinetic profiles after single and multiple dose intravenous METH administration are compared for the rat and human. Significant differences in elimination half‐life between the two species (t1/2: rat—70 min, human—12 h) result in markedly dissimilar profiles of METH exposure. However, the plasma profile of a human METH binge pattern can be approximated in the rat by increasing METH dose frequency. Consideration of METH pharmacokinetics in animal models should permit a closer simulation of the temporal profile of METH exposure in the human CNS and should provide further insight into the mechanisms contributing to the addiciton and psychopathology associated with METH abuse. Synapse 39:161–166, 2001.

The Chemical Biology of Naphthoquinones and Its Environmental Implications

Quinones are a group of highly reactive organic chemical species that interact with biological systems to promote inflammatory, anti-inflammatory, and anticancer actions and to induce toxicities. This review describes the chemistry, biochemistry, and cellular effects of 1,2- and 1,4-naphthoquinones and their derivatives. The naphthoquinones are of particular interest because of their prevalence as natural products and as environmental chemicals, present in the atmosphere as products of fuel and tobacco combustion. 1,2- and 1,4-naphthoquinones are also toxic metabolites of naphthalene, the major polynuclear aromatic hydrocarbon present in ambient air. Quinones exert their actions through two reactions: as prooxidants, reducing oxygen to reactive oxygen species; and as electrophiles, forming covalent bonds with tissue nucleophiles. The targets for these reactions include regulatory proteins such as protein tyrosine phosphatases; Kelch-like ECH-associated protein 1, the regulatory protein for NF-E2-related factor 2; and the glycolysis enzyme glyceraldehyde-3-phosphate dehydrogenase. Through their actions on regulatory proteins, quinones affect various cell signaling pathways that promote and protect against inflammatory responses and cell damage. These actions vary with the specific quinone and its concentration. Effects of exposure to naphthoquinones as environmental chemicals can vary with the physical state, i.e., whether the quinone is particle bound or is in the vapor state. The exacerbation of pulmonary diseases by air pollutants can, in part, be attributed to quinone action.

Patterns of methamphetamine abuse and their consequences

Abstract The abuse of methamphetamine (METH) continues to increase throughout all age groups in different regions of the United States. “Ice,” the popularized jargon for (+) methamphetamine hydrochloride, is the predominant drug form that is now consumed. “Ice” is effectively absorbed after either smoking or snorting and it is this rapid influx of drug that produces effects similar to those after intravenous administration. The intensity of METH actions in the central and peripheral nervous system shows tolerance after chronic administration, indicating that neuro-adaptations have occurred. Thus, the physiological processes and corresponding biochemical mechanisms that regulate neuronal function have been changed by METH exposure. These biological alterations contribute to the craving and dependence associated with METH abuse and the withdrawal syndrome upon abstinence. However, these changes in behavior may also result from METH-induced neurotoxicity. This article reviews aspects of METH pharmacokinetics and related molecular pharmacodynamics that represent METH pharmacology and then relates those actions to their potential to produce neurotoxicity in humans.