Renal Metabolism of Acrylonitrile to Cyanide: In Vitro Studies

Mostafa, A.M.A.; Abdel-Naim, Ashraf B.; Abo-Salem, Osama M.; Abdel-Aziz, A.H.; Hamada, Farid M.A.

doi:10.1006/phrs.1999.0502

Cited by 11 publications

(7 citation statements)

References 24 publications

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“…Recent investigation showed that metabolism of AN was markedly increased in hepatic and extrahepatic rat microsomes obtained from animals treated with P450s inducers. This further suggested that multiple P450s may be involved in the metabolism of AN to cyanide (Mostafa et al, 1999). Earlier studies showed that inducers (phenobarbital) and inhibitors (SKF 525A) of P450 enzymes had no effect on thiocyanate excretion in animals (Gut et al, 1975).…”

Section: Acrylonitrile (Anmentioning

confidence: 92%

“…Results from in vitro investigations using chemical modulators of P450s indicated that activation of AN to cyanide was markedly enhanced in microsomes obtained from rats treated with known P450 inducers like phenobarbital, ethanol, and 3-methylcholanthrene (Mostafa et al, 1999). It was concluded that these modulators of P450s were responsible for the increased metabolism of AN to cyanide.…”

Section: Fig 4 Western Blot Analysis Of Immunoreactive Meh and Seh mentioning

confidence: 99%

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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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Section: Acrylonitrile (Anmentioning

confidence: 92%

Section: Fig 4 Western Blot Analysis Of Immunoreactive Meh and Seh mentioning

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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“…With respect to its tissue distribution, the highest constitutive CYP2E1 enzyme levels appear in the liver, but lower levels are also expressed in extrahepatic tissues (Botto et al 1994;Subramanian and Ahmed 1995;Vieira et al 1998;Mostafa et al 1999) and can be of toxicological significance. With respect to its tissue distribution, the highest constitutive CYP2E1 enzyme levels appear in the liver, but lower levels are also expressed in extrahepatic tissues (Botto et al 1994;Subramanian and Ahmed 1995;Vieira et al 1998;Mostafa et al 1999) and can be of toxicological significance.…”

Section: Introductionmentioning

confidence: 99%

The cytochrome P-450 isoenzyme CYP2E1 in the biological processing of industrial chemicals: consequences for occupational and environmental medicine

Bolt

Roos

Thier

2003

Int Arch Occup Environ Health

181

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“…There are very few reports about the immunotoxicity of the hydrogen cyanide; however, acrylonitrile [also known as vinyl cyanide (VCN)], an environmental pollutant that is metabolized to cyanide, has been shown to be an animal and human carcinogen, particularly in the gastrointestinal tract (Mostafa et al, 1999;National Toxicology Program Technical Report Series, 2001). Hamada et al (1998) evaluated the systemic and local immunotoxic potential of VCN and demonstrated that VCN induces immunosuppression, as evident by a decrease in the PFC response to SRBCs, a marked depletion of spleen lymphocyte subsets, and bacterial translocation of the normal flora, leading to brachial lymph node abscess.…”

Section: Immunotoxicitymentioning

confidence: 99%