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ToxSci Advance Access published online on September 1, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi307
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Published by Oxford University Press 2005.
Received May 31, 2005
Accepted August 29, 2005

Biotransformation and Toxicokinetics

Role of CYP2E1 in the Epoxidation of Acrylamide to Glycidamide and Formation of DNA and Hemoglobin Adducts

Burhan I. Ghanayem 1*, L. Patrice McDaniel 2, Mona I. Churchwell 2, Nathan C. Twaddle 2, Rodney Snyder 3, Timothy R Fennell 3, and Daniel R. Doerge 2

1 Laboratory of Pharmacology and Chemistry. National Toxicology Program, NIEHS/NIH, RTP, NC
2 NCTR, Jefferson, AR
3 RTI International, RTP, NC

* To whom correspondence should be addressed.
Burhan I. Ghanayem, E-mail: ghanayem{at}niehs.nih.gov


  Abstract

Acrylamide (AA) is an animal carcinogen, neurotoxin, and reproductive toxin. AA is formed in baked and fried carbohydrate-rich foods. Metabolism of AA occurs via epoxidation to glycidamide (GA) or direct conjugation with glutathione. Using CYP2E1-null mice, recent studies in this laboratory demonstrated that induction of somatic and germ cell mutagenicity in AA-treated mice is dependent on CYP2E1. We hypothesized that AA metabolism to GA is a pre-requisite for the induction of AA-induced mutagenicity. Current studies were undertaken to assess the role of CYP2E1 in the epoxidation of AA to GA and the formation of DNA and hemoglobin (HGB) adducts. AA was administered to CYP2E1-null or wild-type mice at 50 mg/kg IP. Mice were euthanized 6hr later and blood and tissues were collected. Using LCES/ MS/MS, AA, GA, and DNA- and HGB-adducts were measured. While the plasma levels of AA and GA were 115±14.0 and 1.7±0.31µM in CYP2E1-null mice, they were 0.84±0.80 and 33.0±6.3µM in the plasma of AA-treated wild-type mice. Administration of AA to wild-type mice caused a large increase in N7-GA-Gua and N3-GA-Ade adducts in the liver, lung, and testes. While traces of N7-GA-Gua adducts were measured in the tissues of AA-treated CYP2E1-null mice, these levels were 52-66-fold lower than in wild-type mice. Significant elevation of both AA- and GA-HGB adducts was detected in AA-treated wild-type mice. In AAtreated CYP2E1-null mice, levels of AA-HGB adducts were roughly twice as high as those in wild-type mice. In conclusion, current work demonstrated that CYP2E1 is the primary enzyme responsible for the epoxidation of AA to GA, which leads to the formation of GA-DNA and HGB adducts.


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