Metabolism of diphenyl sulfoxide in perfused guinea pig liver. Involvement of aldehyde oxidase as a sulfoxide reductase.
To evaluate the metabolic capacity of intact guinea pig liver under normoxic and hypoxic conditions, oxidative and reductive metabolism of diphenyl sulfoxide (DPSO) was studied by the nonrecirculating perfusion method in situ. DPSO was exclusively converted into diphenyl sulfone (DPSO2), an oxidative metabolite, under normoxia. When diphenyl sulfide (DPS) was infused, DPSO was eliminated as a predominant metabolite. Judging from the susceptibility toward selective inhibitors of cytochrome P-450, both oxidative steps appear to be catalyzed by cytochrome P-450-dependent monooxygenase rather than flavin adenine dinucleotide-containing monooxygenase. Under hypoxic conditions, however, DPSO2 formation was decreased in parallel with reduced oxygen concentration in the influent perfusate, whereas only a trace amount of DPS, a reductive metabolite, was detected. On the other hand, coinfusion of an electron donor for aldehyde oxidase such as 2-hydroxypyrimidine and benzaldehyde, but not xanthine, markedly stimulated the formation of DPS during hypoxia. These results indicate that the oxidative pathway catalyzed by cytochrome P-450-dependent monooxygenase is predominant in DPSO metabolism under normoxic conditions, whereas only under hypoxia does the reductive pathway become the major one if an electron donor for aldehyde oxidase exists in intact guinea pig liver.
Yoshihara
S
S
Institute of Pharmaceutical Science, Hiroshima University School of Medicine, Japan.
Tatsumi
K
K
D042931:Aldehyde Oxidase; D000445:Aldehyde Oxidoreductases / Q000378:metabolism*; D000818:Animals; D001555:Benzene Derivatives / Q000378:metabolism*; D015687:Cell Hypoxia / Q000502:physiology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000378:metabolism*; D050862:Oxidoreductases Acting on Sulfur Group Donors; D010477:Perfusion; D013347:Subcellular Fractions / Q000378:metabolism
D001555:Benzene Derivatives; C048860:diphenyl sulfoxide; D010088:Oxidoreductases; D000445:Aldehyde Oxidoreductases; D042931:Aldehyde Oxidase; D050862:Oxidoreductases Acting on Sulfur Group Donors; C030542:sulfoxide reductase