Cytochrome P-450 heme moiety. The specific target in drug-induced heme alkylation.

Correia, Maria Almira; Farrell, Geoffrey C.; Olson, Stacey; Wong, Jane; Schmid, Roland; Montellano, Paul R. Ortiz de; Beilan, Hal S.; Kunze, Kent L.; Mico, Bruce A.

doi:10.1016/s0021-9258(19)69224-0

Cited by 25 publications

(3 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Site-specific oxidative inactivation is well-known. In a number of studies Ortiz de Mantellano and co-workers (Ortiz de Correia et al, 1981; Ortiz de Mantello et al, 1981; Ortiz de Mantello & Mathews, 1981;Augusto et al, 1982) have observed oxidative covalent inactivation of heme proteins. These covalent inactivations, which proceed through site-generated radicals and by more complex mechanisms, involve reaction of small molecule substrates with heme and less frequently with the side chains of neighboring amino acid residues.…”

Section: Discussionmentioning

confidence: 99%

Affinity-dependent crosslinking to neurotoxin sites of the acetylcholine receptor mediated by catechol oxidation

Nickoloff¹,

Grimes²,

Wohlfeil³

et al. 1985

Biochemistry

View full text Add to dashboard Cite

The choline homologue 3-[(trimethylammonio)methyl]catechol (TMC) has been synthesized, and the controllable features of its complex oxidation have been examined spectroscopically and correlated with its toxin binding inactivating reactions with the acetylcholine receptor (AcChR) from Torpedo californica electroplax. Affinity-dependent reactions of early intermediates in the oxidation of TMC are suggested to intercede covalently in this inactivation. At pH 7.4, where the oxidative polymerization of catechols proceeds spontaneously, pyrocatechol produced no effect on the toxin binding function of AcChR, whereas comparable concentrations of TMC led to inactivation of half of all available sites. Lower concentrations of TMC converted via oxidation with ceric salts to an in situ mixture of monohydroxylated catechols were shown to be effective in short-term incubations in inactivating approximately half of the toxin binding sites by covalent labeling of the receptor. Mixtures of dihydroxycatechol intermediates, hydroxy-p-quinones, and polymeric products led to nonspecific toxin binding site inactivation of AcChR in excess of half of all available sites. Collectively, the results suggest that both covalent labeling and oxygen reduction product inactivating mechanisms are operative in these model macromolecular site reactions and that catechol-containing affinity reagents may be useful in elucidating the molecular features of sites to which they are directed.

show abstract

Section: Discussionmentioning

confidence: 99%

Affinity-dependent crosslinking to neurotoxin sites of the acetylcholine receptor mediated by catechol oxidation

Nickoloff¹,

Grimes²,

Wohlfeil³

et al. 1985

Biochemistry

View full text Add to dashboard Cite

show abstract

“…Finally, the destruction of cytochrome P-450 by ethchlorvynol may be responsible, at least in part, for the increase in heme synthesis associated with this drug and for its contraindication in porphyric patients.7,8 Accelerated heme synthesis could result from derepression of the pathway due to a decrease in the regulatory heme pool mediated by sequential prosthetic heme destruction and replacement. 25 The prosthetic heme adduct may alternatively, like IV-methylprotoporphyrin IX,26-28 inhibit ferrochelatase. Although some prosthetic heme adducts have been reported not to inhibit ferrochelatase,27 we have recently shown that the inhibitory activity depends on which nitrogen is alkylated.…”

Section: Discussionmentioning

confidence: 99%

“…Recrystallization from EtOH/H20 gave a sample: mp 108.5-110 °C; IR vw 2237 cm"1; NMR (CDC13) 3. 25 (br, CH2), 4.2 (br, CH), 7.25 (m, Ph) (imidazole protons not observed due to the presence of paramagnetic impurities). Anal.…”

mentioning

confidence: 99%

Alkylation of the prosthetic heme in cytochrome P-450 during oxidative metabolism of the sedative-hypnotic ethchlorvynol

Pr¹,

Hs²,

Jm³

1982

J. Med. Chem.

View full text Add to dashboard Cite

The clinically used sedative-hypnotic ethchlorvynol destroys hepatic microsomal cytochrome P-450 enzymes in a process catalyzed by the same hemoproteins. Abnormal porphyrins accumulate in the livers of phenobarbital-pretreated rats after administration of ethchlorvynol. The abnormal porphyrin fraction has been isolated and shown to consist of the four possible regioisomers of N-(5-chloro-3-ethyl-3-hydroxy-2-oxo-4-pentenyl)protoporphyrin IX. Cytochrome P-450 inactivation thus appears to result from alkylation of the prosthetic heme by the oxidatively activated acetylenic function in ethchlorvynol. The autocatalytic destruction of the hemoprotein is likely to alter the metabolism and elimination of ethchlorvynol and coadministered drugs and may be the cause of the porphyrinogenic properties of ethchlorvynol.

show abstract

Bioactivation I: Bioactivation by Cytochrome P450s

Dalvie

2012

Encyclopedia of Drug Metabolism and Interactions

View full text Add to dashboard Cite

Metabolism reactions generally result in detoxification of xenobiotics and are accompanied by the formation of chemically stable metabolites, which are devoid of pharmacological or toxicological activities. However, in some cases, these reactions can convert drugs to products that are either chemically reactive or pharmacologically active, a process that is commonly referred to as metabolic activation or bioactivation . Most, if not all, functionalization and conjugation reactions can result in bioactivation. Even though all enzymes have the propensity to catalyze the metabolic activation of compounds, cytochrome P450 (P450) enzymes, which generally dominate metabolism, play a major role in the metabolic activation of drugs. The primary objective of this chapter is to provide an overview of bioactivation by P450 to pharmacologically active and chemically reactive metabolites. The common reactions that result in bioactivation of xenobiotics and consequences of bioactivation have been discussed here.

show abstract

Cytochrome P-450 heme moiety. The specific target in drug-induced heme alkylation.

Cited by 25 publications

References 34 publications

Affinity-dependent crosslinking to neurotoxin sites of the acetylcholine receptor mediated by catechol oxidation

Affinity-dependent crosslinking to neurotoxin sites of the acetylcholine receptor mediated by catechol oxidation

Alkylation of the prosthetic heme in cytochrome P-450 during oxidative metabolism of the sedative-hypnotic ethchlorvynol

Bioactivation I: Bioactivation by Cytochrome P450s

Contact Info

Product

Resources

About