title: An unexpected pathway for the metabolic degradation of 1,3-dialkyl-3-acyltriazenes.
abstract: In the presence of NADPH, rat liver microsomes catalyzed the degradation of a series of 1,3-dialkyl-3-acyltriazenes, and the extent of the reaction was correlated with compound lipophilicity. In the case of two methylcarbamoyltriazenes, 1-(2-chloroethyl)-3-benzyl-3- (methylcarbamoyl)triazene (CBzM) and 1-(2-chloroethyl)-3-methyl-3-(methylcarbamoyl)triazene (CMM), microsomal metabolites were isolated. Identification of the CBzM metabolites as 1-(2-chloroethyl)-3-benzyl-3-(hydroxymethylcarbamoyl)triazene and 1-(2-chloroethyl-3-benzyl-3-carbamoyltriazine, and the CMM metabolite as 1-(2-chloroethyl)-3-methyl-3-(hydroxymethylcarbamoyl)triazene indicated that the first metabolic step involves hydroxylation of the methylcarbamoyl substituent. Detailed studies of the metabolism of CBzM indicated that the Km for the reaction was 84 microM, and that metabolism was more efficient if microsomes were prepared from male than from female rats. During prolonged incubation, the metabolites of CBzM were also degraded. The degradation of CBzM and its metabolites was inhibited by SKF-525A and metyrapone, suggesting the involvement of a cytochrome P450 isozyme, and supporting the hypothesis that the process is oxidative rather than hydrolytic in both cases. Metabolic oxidation represents an alternative pathway to chemical or enzymatic hydrolysis for the in vivo decomposition of (methylcarbamoyl)triazenes. This mechanism may ultimately explain the antitumor efficacy and low acute toxicity of selected compounds.
authors.affiliation: Department of Chemistry, Western Maryland College, Westminster 21157.
authors.forename: C A
authors.initials: CA
authors.lastname: Rouzer
authors.forename: E J
authors.initials: EJ
authors.lastname: Thompson
authors.forename: T L
authors.initials: TL
authors.lastname: Skinner
authors.forename: P A
authors.initials: PA
authors.lastname: Heavner
authors.forename: W P
authors.initials: WP
authors.lastname: Bartolini
authors.forename: K
authors.initials: K
authors.lastname: Mitchell
authors.forename: E
authors.initials: E
authors.lastname: Kurz
authors.forename: R H
authors.initials: RH
authors.lastname: Smith
authors.forename: C J
authors.initials: CJ
authors.lastname: Michejda
mesh_terms: D000477:Alkylating Agents / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D010084:Oxidation-Reduction; D051381:Rats; D011916:Rats, Inbred F344; D014226:Triazenes / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000477:Alkylating Agents; D000970:Antineoplastic Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D014226:Triazenes; C082496:1-(2-chloroethyl)-3-benzyl-3-(methylcarbamoyl)triazene; D003577:Cytochrome P-450 Enzyme System