Reactive metabolites in the biotransformation of molecules containing a furan ring

Abstract

Many xenobiotics containing a furan ring are toxic and/or carcinogenic. The harmful effects of these compounds require furan ring oxidation. This reaction generates an electrophilic intermediate. Depending on the furan ring substituents, the intermediate is either an epoxide or a cis-enedione with more ring substitution favoring epoxide formation. Either intermediate reacts with cellular nucleophiles such as protein or DNA to trigger toxicities. The reactivity of the metabolite determines which cellular nucleophiles are targeted. The toxicity of a particular furan is also influenced by the presence of competing metabolic pathways or efficient detoxification routes. GSH plays an important role in modulating the harmful effects of this class of compound by reacting with the reactive metabolite. However, this may not represent a detoxification step in all cases.

Scheme 1

Oxidation of furan by P450 enzymes to either an epoxide 1 or a cis-enedione 3 metabolite and their reaction with GSH.^,

Scheme 2

Trapping of the reactive metabolite formed in the P450-catalyzed oxidation of furan in microsomes.^,

Scheme 3

Pathways of in vivo metabolism of furan.^,–

Scheme 4

Metabolites formed from furan in rat hepatocytes.^,

Scheme 5

Structure of BDA-derived DNA adducts.^–

Scheme 6

Trapping of the reactive metabolite formed in the P450-catalyzed oxidation of 2-methylfuran in microsomes.

Scheme 7

Reaction of 4-oxo-2-pentenal with 2′-deoxyguanosine. ^,

Scheme 8

Microsomal metabolism of the furan ring of furosemide.^,

Scheme 9

Biliary and hepatocyte metabolites of furosemide.

Scheme 10

Metabolites derived from furanyl ring oxidation of prazosin.^,

Scheme 11

Trapping the reactive metabolite of 3-methylfuran as a bis-semicarbazone.

Scheme 12

Structures of the GSH reaction products formed in GSH-fortified microsomal incubations of 4-ipomeanol.^,,

Scheme 13

Trapping of reactive intermediate formed in N-acetylcysteine (NAC)/N-acetyllysine (NAL) fortified microsomal incubations of 4-ipomeanol.

Scheme 14

Products formed during the microsomal oxidation of L-739,010 in the presence of semicarbazide and required co-factors.^,

Scheme 15

Reactive intermediates in teucrin A metabolism and the reaction products between teucrin A enedial and N-acetylcysteine (NAC) and/or N-acetyl-lysine (NAL).

Scheme 16

Mechanisms of metabolite formation from the proposed epoxide intermediate of menthofuran.^,–

Scheme 17

Metabolism of bergamottin to a reactive metabolite.

Scheme 18

Products of furanyl ring oxidation of L-754,394 in the presence and absence of trapping agents.