Effects of 3-(2-phenylethyl)-4-methylsydnone and related sydnones on heme biosynthesis.
3-[2-(2,4,6-Trimethylphenyl)thioethyl]-4-methylsydnone (TTMS) and 3-(2-phenylethyl)-4-methylsydnone (PEMS) cause mechanism-based inactivation of rat hepatic microsomal cytochrome P-450 and the formation of N-alkylprotoporphyrins in rat liver. In the present study, we have shown that both TTMS and PEMS cause mechanism-based inactivation of chick embryo hepatic microsomal cytochrome P-450. TTMS also caused the inhibition of ferrochelatase activity, the accumulation of protoporphyrin IX, and an increase in the activity of delta-aminolevulinic acid synthase in chick embryo liver cell culture. PEMS was devoid of effect on ferrochelatase activity, porphyrin accumulation, and delta-aminolevulinic acid synthase activity. There are two possible explanations for the lack of effect of PEMS on heme biosynthesis: (1) the ring-A- and/or ring-B-substituted regiosomers of the N-phenylethyl- and N-phenylethenylprotoporphyrins which are produced during the mechanism-based inactivation of cytochrome P-450 by PEMS are too bulky to fit into the active site of ferrochelatase to inhibit its activity, in contrast to the N-vinylprotoporphyrin formed from TTMS; and (2) the N-alkylprotoporphyrins produced consist of the ring-C- and/or ring-D-substituted regioisomers, which are not inhibitors of ferrochelatase activity.
Mackie
J E
JE
Department of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada.
Ortiz de Montellano
P R
PR
Grab
L A
LA
Marks
G S
GS
D000624:5-Aminolevulinate Synthetase / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D002642:Chick Embryo; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005294:Ferrochelatase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006418:Heme / Q000096:biosynthesis*; D008099:Liver / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D008862:Microsomes, Liver / Q000201:enzymology; D015394:Molecular Structure; D010069:Oxadiazoles / Q000494:pharmacology*; D011166:Porphyrins / Q000378:metabolism; D013558:Sydnones / Q000494:pharmacology*
D065607:Cytochrome P-450 Enzyme Inhibitors; D010069:Oxadiazoles; D011166:Porphyrins; D013558:Sydnones; C057213:3-(2-phenylethyl)-4-methylsydnone; D006418:Heme; C048192:3-(2-(2,4,6-trimethylphenyl)thioethyl)-4-methylsydnone; D003577:Cytochrome P-450 Enzyme System; D000624:5-Aminolevulinate Synthetase; D005294:Ferrochelatase