Abstract:
:Indirect evidence for the participation of cytochrome P450 (P450) in the microsomal N-oxygenation of primary and N-substituted amine functions is presented by studies employing diagnostic modifiers of the hemoprotein system as well as immunochemical approaches. Experiments with recombinant hemoproteins or isozymes purified from the tissues of various animal species support the results obtained by the inhibitor assays. Amine substrates and the redox proteins of the microsomal electron transfer chain reveal to be mutually beneficial in interactions with P450s. Numerous N-substituted amines undergo P450-catalyzed N-oxidative transformation despite the presence of accessible alpha-C hydrogens in these structures rather thought to favor N-dealkylation. In these instances, stabilization of the initially formed aminium radicals by the specific active site orientation of the particular P450s obviously permits oxygen rebound. Apart from common iron-oxenoid chemistry involving a (FeO)3+ species, iron-bound hydroperoxide, (FeO2H)3+, appears to act as an electrophilic oxidant with certain N-substituted amines and P450 subforms. Generally, P450-mediated N-oxygenation of amines can produce cytotoxic and mutagenic metabolites, but equally can well yield hydrophilic products, that are readily excreted and thus promote detoxication.
journal_name
Drug Metab Revjournal_title
Drug metabolism reviewsauthors
Hlavica Pdoi
10.1081/dmr-120005646keywords:
subject
Has Abstractpub_date
2002-08-01 00:00:00pages
451-77issue
3eissn
0360-2532issn
1097-9883journal_volume
34pub_type
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