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SHORT COMMUNICATION

FORMATION OF N-ALKYLPROTOPORPHYRIN IX FROM METABOLISM OF DIALLYL SULFONE IN LUNG AND LIVER

Department of Anatomy and Cell Biology, Queen's University, Kingston, Ontario, Canada

Diallyl sulfone (DASO₂) is a garlic derivative formed during cooking or after ingestion. Bioactivation of DASO₂ in murine lung and liver results in formation of an epoxide that inactivates CYP2E1 and significantly decreases cytochrome P450 and heme levels. In this study, we tested the hypothesis that DASO₂ metabolism leads to production of the heme adduct, N-alkylprotoporphyrin IX (N-alkylPP). Formation of N-alkylPP in vivo and in vitro was determined by spectrophotometric and fluorometric methods, respectively. In in vivo studies, N-alkylPP was generated in the livers of male and female mice treated with DASO₂, but was not detectable in the lungs of DASO₂-treated mice. In in vitro studies, rates of formation of N-alkylPP in liver and lung microsomes incubated with DASO₂ and NADPH were dependent on time and protein concentrations, but were negligible in control incubations performed in the absence of NADPH or DASO₂ or with boiled microsomes. The rates of N-alkylPP formation generated in murine liver were higher than those in either murine lung or human liver. Kinetic analysis revealed that murine liver microsomes metabolized DASO₂ to N-alkylPP with higher affinity and catalytic efficiency than did murine lung or human liver microsomes. Recombinant rat CYP2E1 also metabolized DASO₂ to N-alkylPP; however, rates of formation of the heme adduct was minimal in incubations of recombinant human CYP2E1 with DASO₂. These findings demonstrated that the N-alkylPP adduct was produced via metabolism of DASO₂ in murine liver and lung microsomes, in human liver microsomes, in recombinant CYP2E1, and in vivo in murine liver.

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