Epoxidation of acrylonitrile by rat and human cytochromes P450

Kedderis, Gregory L.; Batra, Renu; Koop, Dennis R.

doi:10.1021/tx00036a017

Cited by 53 publications

(36 citation statements)

References 33 publications

(57 reference statements)

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“…These findings are consistent with earlier in vitro studies with human and rat hepatic microsomes, which indicated that CYP2E1 is the major catalyst of AN epoxidation (27,34). In contrast to the earlier in vitro studies (34) (23). Assessment of …”

Section: Introductionsupporting

confidence: 92%

“…In wild-type mice, AN is metabolized to CEO, and both AN and CEO conjugate with glutathione, resulting in the excretion of a number of mercapturic acids ( Figure 2 (72). These findings are consistent with earlier in vitro studies with human and rat hepatic microsomes, which indicated that CYP2E1 is the major catalyst of AN epoxidation (27,34). In contrast to the earlier in vitro studies (34) (23).…”

Section: Introductionsupporting

confidence: 85%

“…' studies therefore investigated the toxicity of acetaminophen in CYP1A2 and CYP2E1 double-null mice (79 (78). AN has been shown to be metabolized to 2-cyanoethylene oxide (CEO) (Figure 2), and in vitro studies have implicated CYP2E1 as the major isozyme (26,27,34). Oxidative metabolism is believed to play a significant role in the toxicity and carcinogenicity of this chemical (34).…”

Section: Introductionmentioning

confidence: 99%

“…AN has been shown to be metabolized to 2-cyanoethylene oxide (CEO) (Figure 2), and in vitro studies have implicated CYP2E1 as the major isozyme (26,27,34). Oxidative metabolism is believed to play a significant role in the toxicity and carcinogenicity of this chemical (34). In wild-type mice, AN is metabolized to CEO, and both AN and CEO conjugate with glutathione, resulting in the excretion of a number of mercapturic acids ( Figure 2 (72).…”

Section: Introductionmentioning

confidence: 99%

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Using Cytochrome P-450 Gene Knock-Out Mice to Study Chemical Metabolism, Toxicity, and Carcinogenicity

2000

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Cytochrome P-450 (CYP) enzymes are heme-containing proteins that carry out oxidative metabolism of a wide range of structurally diverse exogenous chemicals and therapeutic agents as well as endogenous compounds. For some of these xenobiotics, oxidative metabolism results in the formation of toxic, mutagenic, or carcinogenic metabolites. In the past, the role of CYP enzymes in metabolism and chemical-induced toxicity was studied indirectly through use of specific antibodies or inducers and inhibitors of these enzymes. Progress in molecular biology and the ability to bioengineer animal models that do not express CYP1A2, CYP1A1, CYP1B1, CYP2E1, or both CYP1A2 and CYP2E1 isozymes has allowed for direct investigations of the in vivo role of these enzymes in the metabolism, toxicity, and carcinogenicity of xenobiotics. This article reviews research conducted to date that utilizes these genetically bioengineered mice in metabolism, toxicity, or carcinogenicity studies of chemicals. Some studies showed a positive correlation between in vivo results and in vitro predictions for the role of a specific CYP in chemical-induced effects, whereas other studies did not support in vitro predictions. Work reviewed herein demonstrates the importance of using animal models for investigating the role of specific CYP enzymes in metabolism and chemical-induced toxicity or carcinogenicity rather than relying solely on in vitro techniques. Eventually, studies of this nature will facilitate a more accurate assessment of human risks with regard to chemicals by helping us to understand the relationships between chemical metabolism, carcinogenicity, and polymorphisms in CYP enzymes.

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Section: Introductionsupporting

confidence: 92%

Section: Introductionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Using Cytochrome P-450 Gene Knock-Out Mice to Study Chemical Metabolism, Toxicity, and Carcinogenicity

2000

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“…It was suggested that whereas CYP2E1 plays a major role in the metabolism of AN to CEO, other cytochrome P450s (P450s) are also involved (Guengerich et al, 1991;Kedderis et al, 1993;Subramanian and Ahmed, 1995). Recent investigation showed that metabolism of AN was markedly increased in hepatic and extrahepatic rat microsomes obtained from animals treated with P450s inducers.…”

Section: Acrylonitrile (Anmentioning

confidence: 99%

Cytochrome P450 2E1 (CYP2E1) is Essential for Acrylonitrile Metabolism to Cyanide: Comparative Studies Using CYP2E1-Null and Wild-Type Mice

Wang

Chanas²,

Ghanayem³

2002

Drug Metab Dispos

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ABSTRACT:Acrylonitrile (AN) is a rodent carcinogen and suspected human carcinogen. Metabolism of AN proceeds via conjugation with glutathione or epoxidation via cytochrome P4502E1 (CYP2E1) to cyanoethylene oxide (CEO). It was hypothesized that CEO metabolism via epoxide hydrolase (EH) is the primary pathway for cyanide formation. The objective of this work is to assess the enzymatic basis of metabolism to cyanide. Male wild-type and CYP2E1-null mice received 0, 2.5, 10, 20, or 40 mg of AN/kg by gavage, and cyanide was measured in blood and tissues. CYP2E1 and EH expression were assessed using Western blot analyses. Present results demonstrated that cyanide concentrations in blood and tissues of AN-treated wild-type mice were higher at 1 versus 3 h, increased in a dose-dependent manner, and were significantly higher in AN-treated versus vehicle-treated mice. In contrast, cyanide concentrations in the blood and tissues of AN-treated CYP2E1-null mice were not statistically different from those of vehicle-treated mice. Furthermore, this work showed that EH is expressed in CYP2E1-null and wild-type mice. In conclusion, under the current experimental conditions using CYP2E1-null mice, current work demonstrated for the first time that CYP2E1-mediated oxidation is a prerequisite for AN metabolism to cyanide. Since earlier studies showed that CYP2E1 is the only enzyme responsible for AN epoxidation, it is concluded that AN metabolism to CEO is a prerequisite for cyanide formation, and this pathway is exclusively catalyzed by CYP2E1. Finally, this work confirmed that cyanide plays an essential role in the causation of the acute toxicity/mortality of AN.

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Acetone

Morgott¹

2001

Patty's Toxicology

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Acetone is a clear, colorless liquid that is highly flammable and infinitely soluble in water. Years of clinical study, laboratory testing, and practical experience have shown that acetone can be used safely and without harm in many industrial and commercial applications. The long‐standing interest in the biochemical, pharmacological, and toxicological properties of acetone can be traced to three important characteristics of the chemical: Acetone is a normal by‐product of mammalian metabolism; levels within the body can, however, be altered by changes in nutrition or energy balance. Acetone is a highly volatile organic solvent that is miscible with water; thus large amounts of the vapor can be absorbed through the lungs and quickly distributed throughout the body. Acetone is manufactured and used in large amounts in a variety of commercial and industrial applications; thus the potential for exogenous human exposure is widespread.

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Epoxidation of acrylonitrile by rat and human cytochromes P450

Cited by 53 publications

References 33 publications

Using Cytochrome P-450 Gene Knock-Out Mice to Study Chemical Metabolism, Toxicity, and Carcinogenicity

Using Cytochrome P-450 Gene Knock-Out Mice to Study Chemical Metabolism, Toxicity, and Carcinogenicity

Cytochrome P450 2E1 (CYP2E1) is Essential for Acrylonitrile Metabolism to Cyanide: Comparative Studies Using CYP2E1-Null and Wild-Type Mice

Acetone

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