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

• Published in: Drug metabolism and disposition Vol. 34; no. 6; pp. 895 - 900
• Main Authors: BLACK, Gordon P, COLLINS, Kathy S, BLACQUIERE, Dylan P, FORKERT, Poh-Gek
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01.06.2006
• Subjects: Alkylation; Allyl Compounds - administration & dosage; Allyl Compounds - metabolism; Animals; Biological and medical sciences; Cytochrome P-450 CYP2E1 - genetics; Cytochrome P-450 CYP2E1 - metabolism; Female; Humans; Kinetics; Liver - metabolism; Lung - metabolism; Male; Medical sciences; Mice; Microsomes, Liver - metabolism; Pharmacology. Drug treatments; Protoporphyrins - biosynthesis; Protoporphyrins - chemistry; Protoporphyrins - metabolism; Recombinant Proteins - metabolism; Sex Factors; Sulfones - administration & dosage; Sulfones - metabolism; Sulfone; Digestive system; Liver; Lung; Pharmacokinetics; Metabolism; Respiratory system
• ISSN: 0090-9556; 1521-009X
• DOI: 10.1124/dmd.106.009928

Diallyl sulfone (DASO 2 ) is a garlic derivative formed during cooking or after ingestion. Bioactivation of DASO 2 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 DASO 2 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 DASO 2 , but was not detectable in the lungs of DASO 2 -treated mice. In in vitro studies, rates of formation of N -alkylPP in liver and lung microsomes incubated with DASO 2 and NADPH were dependent on time and protein concentrations, but were negligible in control incubations performed in the absence of NADPH or DASO 2 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 DASO 2 to N -alkylPP with higher affinity and catalytic efficiency than did murine lung or human liver microsomes. Recombinant rat CYP2E1 also metabolized DASO 2 to N -alkylPP; however, rates of formation of the heme adduct was minimal in incubations of recombinant human CYP2E1 with DASO 2 . These findings demonstrated that the N -alkylPP adduct was produced via metabolism of DASO 2 in murine liver and lung microsomes, in human liver microsomes, in recombinant CYP2E1, and in vivo in murine liver.