Cytochrome suicide inhibitors

Mathews JM, Bend JR. N-alkylaminobenzotriazoles as isozyme-selective suicide inhibitors of rabbit pulmonary microsomal cytochrome P-450. Mol Pharmacol 1986 30(l) 25-32. 

Suicide inhibitors have been reviewed by Rando (1974), Metcalf (1981) and Walsh (1982, 1984). Suicide inhibitors of cytochrome P450s have been reviewed by Ortiz de Montellano (1988). 

Ethynylpyrene, a suicide inhibitor of cytochrome P-450 dependent benzo[a]pyrene hydroxylase activity in liver microsomes. Biochemistry 23, 3827-3836. 

Gan, L.-S.L, A.L. Acebo, and W.L. Alworth (1984). 1-Ethynylpyrene, a suicide inhibitor of cytochrome P-450 dependent benzo(a)pyrene hydroxylase activity in liver microsomes. Biochemistry 23, 3827-3836. 

Ethynylpyrene (Scheme 13) was the first analog of benzo(a)pyrene that was tested as an inhibitor of benzo(a)pyrene hydroxylase. This ethynyl polycyclic aromatic hydrocarbon (PAH) is a very potent in vitro suicide inhibitor of cytochrome P450 lA mediated oxidations of The inhibitory property has been attributed to the drug s fitting... 

Structure-activity relationship studies of ethynyl-PAH compounds (Scheme 13) showed that, while all compounds that were tested were competitive inhibitors of cytochrome P450 1 A, only very few analogs inhibited the enzyme in a mechanism-based fashion. Thus, while methyl-1-pyrenylacetylene and 3-ethynylperylene are suicide inhibitors of benzo(a)pyrene hydroxylation, phenyl-1-pyrenylacetylene is only a competitive inhibitor . ... 

Numerous ethynyl PAHs have been tested as potential inhibitors of the in vitro dealkylation of 7-ethoxyphenoxazone and 7-pentoxyphenoxazone, specific substrates for cytochrome P450 1A and cytochrome P450 2B1, respectivelyThe results show that 1-ethynylpyrene was the most potent suicide inhibitor of cytochrome P450 lA while the... 

Another class of cytochrome P-450 inhibitors, compounds with a monosubstituted acetylenic function, are well known for their potential as insecticide synergists (21) and some have already been reported to be active as JH biosynthesis inhibitors as well (19, 22). Ortiz de Montellano and Kunze (23) have shown that many ethynyl substrates cause the destruction of rat hepatic cytochrome P-450, when the prosthetic heme is alkylated during attempted metabolism of the triple bond. Such suicide substrates must bind to the enzyme and be catalytically acceptable thereby offering a potential for selectivity. In fact, selectivity of suicide substrates for particular molecular forms (isozymes) of hepatic... 

Nagahisa, A., W.H. Orme-Johnson, and S.R. Wilson (1984). Silicon mediated suicide inhibition An efficient mechanism-based inhibitor of cytochrome P-450j,j, oxidation of cholesterol. J. Am. Chem. Soc. 106, 1166-1167. 

Further biotransformations of A VPA involve both the liver microsomal cytochrome P-450 enzymes and the fatty acid 3-oxidation pathway (Fig. 32.28). The mixed-function oxidase system metabolizes the unsaturated metabolite to a y-butyrolactone derivative through a chemically reactive entity that is a suicide-substrate inhibitor of cytochrome P-450. The alkylation of the prosthetic haem by means of the radical occurs prior to the formation of the epoxide. Thus the epoxide is not involved in the cytochrome P-450 inhibition. 

As already mentioned, 2-ethynylnaphthalene was a weak inhibitor of cytochrome P450 1A but exhibited potent inhibitory activity of cytochrome P450 2B1. It was also shown to be a potent inhibitor of 2-naphthylamine N-oxidation in vitro, a reaction mediated by cytochrome P450 1A2. Of the two isomers, 2-ethynylnaphthalene was more potent than 1-ethynylnaphthalene. The mechanism of inhibition of cytochrome P450 1A2 proved to be suicide inhibition ". ... 

Although my Laboratory has used these principles to study the toxicities caused by large doses of drugs, there is every reason to believe that these principles will be equally applicable in studying species differences in the effects of pesticides. Indeed, it is now believed that compounds such as piperonyl butoxide and parathion inhibit cytochrome P-450 enzymes through the formation of chemically reactive metabolites. The specificity of the effects of these substances presumably occurs either because the chemically reactive metabolites have an unusually high affinity for the cytochrome P-450 enzymes or because they are so shortlived that they never leave the immediate environment of the active sites of the enzymes. The use of other "suicide enzyme inhibitors" offers exciting possibilities. 

Zou AR Ma YH, Sui ZH, Ortiz de Montellano PR, Clark JE, Masters BS, Roman RJ (1994) Effects of 17-octadecynoic acid, a suicide-substrate inhibitor of cytochrome P450 fetty acid i--hydroxylase, on renal function in rats. J Pharmacol Exp Therap 268 474 81... 

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