Effect of exposure to four organic solvents on hepatic cytochrome P450 isozymes in rat

Wang, Rui-Sheng; Nakajima, Tamie; Honma, Takeshi

doi:10.1016/0009-2797(95)03673-3

Cited by 22 publications

(11 citation statements)

References 28 publications

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“…These findings could perhaps explain the fact that alcohol abuse and smoking interact synergistically as etiological factors for cancers (Garro and Lieber, 1990). Furthermore, because CYP2E1 substrates are commonly found in the industrial workplace (Raucy et al, 1993;Wang et al, 1996), smokers in these environments may be more sensitive to chemical injury than nonsmokers.…”

mentioning

confidence: 99%

Rat Hepatic CYP2E1 Is Induced by Very Low Nicotine Doses: An Investigation of Induction, Time Course, Dose Response, and Mechanism

Micu

Miksys

Sellers

et al. 2003

J Pharmacol Exp Ther

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CYP2E1 is an ethanol-and drug-metabolizing enzyme that can also activate procarcinogens and hepatotoxicants and generate reactive oxygen species; it has been implicated in the pathogenesis of liver diseases and cancer. Cigarette smoke increases CYP2E1 activity in rodents and in humans and we have shown that nicotine (0.1-1.0 mg/kg s.c. ϫ 7 days) increases CYP2E1 protein and activity in the rat liver. In the current study, we have shown that the induction peaks at 4 h postnicotine (1 mg/kg s.c. ϫ 7 days) treatment and recovers within 24 h. No induction was observed after a single injection, and 18 days of treatment did not increase the levels beyond that found at 7 days. We found that CYP2E1 is induced by very low doses of chronic (ϫ 7 days) nicotine with an ED 50 value of 0.01 mg/kg s.c.; 0.01 mg/kg in a rat model results in peak cotinine levels (nicotine metabolite) similar to those found in people exposed to environmental tobacco smoke (passive smokers; 2-7 ng/ml). Previously, we have shown no change in CYP2E1 mRNA, and our current mechanistic study indicates that nicotine does not regulate CYP2E1 expression by protein stabilization. We postulated that a nicotine metabolite could be causing the induction but found that cotinine (1 mg/kg ϫ 7 days) did not increase CYP2E1. Our findings indicate that nicotine increases CYP2E1 at very low doses and may enhance CYP2E1-related toxicity in smokers, passive smokers, and people treated with nicotine (e.g., smokers, patients with Alzheimer's disease, ulcerative colitis or Parkinson's disease).

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mentioning

confidence: 99%

Rat Hepatic CYP2E1 Is Induced by Very Low Nicotine Doses: An Investigation of Induction, Time Course, Dose Response, and Mechanism

Micu

Miksys

Sellers

et al. 2003

J Pharmacol Exp Ther

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“…Other investigators (Pathiratne et al, 1986;Wang et al, 1996) have reported induction of hepatic CYP2E1 activity by benzene exposures that were orders of magnitude higher (~4000 ppm and ~1500 mg/kg, respectively) than that used in our experiments.…”

Section: Cyp2e1 Activitymentioning

confidence: 59%

Effect of Cyp2e1 Induction by Ethanol on the Immunotoxicity and Genotoxicity of Extended Low-Level Benzene Exposure

Bk²,

Ha³

et al. 2000

Journal of Toxicology and Environmental Health, Part A

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Potential additive effects of ethanol consumption, a common life-style factor, and low-level benzene exposure, a ubiquitous environmental pollutant, were investigated. Ethanol is a potent inducer of the cytochrome P-450 2E1 (CYP2E1) enzyme, which bioactivates benzene to metabolites with known genotoxicity and immunotoxicity. A liquid diet containing 4.1% ethanol was used to induce hepatic CYP2E1 activity by 4-fold in female CD-1 mice. Groups of ethanol-treated or pair-fed control mice were exposed to benzene or filtered air in inhalation chambers for 7 h/d, 5 d/wk for 6 or 11 wk. The initial experiment focused on immunotoxicity endpoints based on literature reports that ethanol enhances high-dose benzene effects on spleen, thymus, and bone marrow cellularity and on peripheral red blood cell (RBC) and white blood cell (WBC) counts. No statistically significant alterations were found in spleen lymphocyte cellularity, subtype profile, or function (mitogen-induced proliferation, cytokine production, or natural killer cell lytic activity) after 6 wk of ethanol diet, 0.44 ppm benzene exposure, or both. This observed absence of immunomodulation by ethanol alone, a potential confounding factor, further validates our previously established murine model of sustained CYP2E1 induction by dietary ethanol. Subsequent experiments involved a 10-fold higher benzene level for a longer time of 11 wk and focused on genotoxic endpoints in known target tissues. Bone marrow and spleen cells were evaluated for DNA-protein cross-links, a sensitive transient index of genetic damage, and spleen lymphocytes were monitored for hprt-mutant frequency, a biomarker of cumulative genetic insult. No treatment-associated changes in either genotoxic endpoint were detected in animals exposed to 4.4 ppm benzene for 6 or 11 wk with or without coexposure to ethanol. Thus, our observations suggest an absence of genetic toxicity in CD-1 mice exposed to environmentally relevant levels of benzene with or without CYP2E1 induction.

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“…Although our findings were consistent with those reported previously [12][13][14]22], the kinetics of the test substances were affected by TCY to a variable extent. Wang et al [6] have reported significant increases in the activities of nitrosodimethylamine demethylase and 7-pentoxyresorufin-O-depentylase after acute inhalational exposure to TCY. For the longer-term exposure the cytochrome P-450 content together with some cytochrome P-450 activities including aminopyrine N-demethylase and aniline hydroxylase [23] or phenobarbital-inducible forms were found to be increased [24].…”

Section: Discussionmentioning

confidence: 99%

“…TCY has presented an increasing potential for a health risk and an environmental problem [2][3][4]. TCY is metabolized by a microsomal mixed-function oxidase system, chiefly by cytochrome P-450s [5][6][7]. The main metabolites have been identified as trichloroethanol and trichloroacetic acid [8], and metabolism also results in the formation of an epoxide intermediate, a chemical species often involved in cell injuries and initiation of carcinogenesis [9,10].…”

Section: Introductionmentioning

confidence: 99%

Alteration of Drug Kinetics in Rats following Exposure to Trichloroethylene

Kukongviriyapan¹,

Simajareuk²,

Kukongviriyapan³

et al. 2001

Pharmacology

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The effect of trichloroethylene (TCY) was investigated to determine whether repeated exposure alters the pharmacokinetics of some drugs. Sprague-Dawley rats were given intraperitoneal injections of TCY (5 mmol/kg) in corn oil once daily for 3 days, while the control group received only corn oil. Four hours after the last dose, theophylline, quinidine, or pentobarbital were administered. Blood samples were collected at appropriate intervals for drug analyses. There was a small decrease in plasma clearance of theophylline, with no change in volume of distribution (V_d) as compared with controls. For quinidine, the elimination half-life was unchanged, and the V_d was decreased by 40%. The clearance of pentobarbital was decreased by 40% in male rats, but not in the females. Nonetheless, the duration of the sleeping time for both sexes was remarkably prolonged as compared with the control group. There was a decrease in the cytochrome P-450 content only in male rats. In conclusion, exposure to TCY causes changes in some drug kinetics, probably resulting from differential effects on the drug-metabolizing enzymes.

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Effect of exposure to four organic solvents on hepatic cytochrome P450 isozymes in rat

Cited by 22 publications

References 28 publications

Rat Hepatic CYP2E1 Is Induced by Very Low Nicotine Doses: An Investigation of Induction, Time Course, Dose Response, and Mechanism

Rat Hepatic CYP2E1 Is Induced by Very Low Nicotine Doses: An Investigation of Induction, Time Course, Dose Response, and Mechanism

Effect of Cyp2e1 Induction by Ethanol on the Immunotoxicity and Genotoxicity of Extended Low-Level Benzene Exposure

Alteration of Drug Kinetics in Rats following Exposure to Trichloroethylene

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