Thianthrene 5-oxide as a probe of the electrophilicity of hemoprotein oxidizing species.
Thianthrene 5-oxide (T-5-O), which is oxidized to the 5,10- and 5,5-dioxides, respectively, by electrophilic and nucleophilic agents, has been used to determine the electronic properties of hemoprotein oxidizing species. Cytochrome P450 oxidizes T-5-O to the 5,10- rather than the 5,5-dioxide but oxidizes the 5,5-dioxide rapidly and the 5,10-dioxide slowly to the 5,5,10-trioxide. Chloroperoxidase oxidizes T-5-O to the 5,10-dioxide but very poorly oxidizes it further to the 5,5,10-trioxide. It does, however, readily oxidize the 5,5-dioxide to the trioxide. The oxidizing species of cytochrome P450 and chloroperoxidase are thus comparably electrophilic, but the former is more powerful. T-5-O is not detectably oxidized by horseradish peroxidase/H2O2 but is oxidized exclusively to the 5,5-dioxide when the peroxide is replaced by dihydroxyfumaric acid (DHFA). The oxygen incorporated into the 5,5-dioxide in this reaction derives from molecular oxygen. This is consistent with the involvement of a DHFA-derived co-oxidizing species. Oxidation of T-5-O by human hemoglobin and H2O2 yields the 5,5- and 5,10-dioxides and the 5,5,10-trioxide. The oxygen in these products derives primarily (greater than 80%) from H2O2. Hemoglobin and H2O2 thus form both a P450-like electrophilic oxidant (5,10-dioxide) and a peroxide-derived nucleophilic oxidant (5,5-dioxide). A large difference in the cis:trans ratios of the 5,10-dioxides produced from T-5-O by cytochrome P450 (1.3:1) and chloroperoxidase (2.5:1) vs hemoglobin (0.1:1) suggests that the hemoglobin active site severely constrains the geometry of the electrophilic oxidation.(ABSTRACT TRUNCATED AT 250 WORDS)
Alvarez
J C
JC
Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco 94143-0446.
Ortiz de Montellano
P R
PR
D000818:Animals; D002711:Chloride Peroxidase / Q000378:metabolism*; D003499:Cyclic S-Oxides / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006420:Hemeproteins / Q000378:metabolism*; D006454:Hemoglobins / Q000378:metabolism*; D006571:Heterocyclic Compounds / Q000378:metabolism*; D006735:Horseradish Peroxidase / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D003499:Cyclic S-Oxides; D006420:Hemeproteins; D006454:Hemoglobins; D006571:Heterocyclic Compounds; C076650:thianthrene 5-oxide; D003577:Cytochrome P-450 Enzyme System; D006735:Horseradish Peroxidase; D002711:Chloride Peroxidase; D010634:Phenobarbital