PT - JOURNAL ARTICLE AU - Gordon P. Black AU - Kathy S. Collins AU - Dylan P. Blacquiere AU - Poh-Gek Forkert TI - FORMATION OF <em>N</em>-ALKYLPROTOPORPHYRIN IX FROM METABOLISM OF DIALLYL SULFONE IN LUNG AND LIVER AID - 10.1124/dmd.106.009928 DP - 2006 Jun 01 TA - Drug Metabolism and Disposition PG - 895--900 VI - 34 IP - 6 4099 - http://dmd.aspetjournals.org/content/34/6/895.short 4100 - http://dmd.aspetjournals.org/content/34/6/895.full SO - Drug Metab Dispos2006 Jun 01; 34 AB - 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. The American Society for Pharmacology and Experimental Therapeutics