title: Rat liver microsomal metabolism of 2-halogenated 4-methylanilines.
abstract: 1. Rat liver microsomal metabolism of 2-fluoro-, 2-chloro- and 2-bromo-4-methylaniline was investigated using h.p.l.c. Metabolites identified include products from side-chain C-hydroxylation (benzyl alcohols and benzaldehydes) and N-hydroxylation (hydroxylamines and nitroso derivatives). Aromatic ring hydroxylation was not a major reaction pathway. 2. A new type of microsomal metabolite was detected which was identified as a secondary amine, i.e. a halogenated N-(4'-aminobenzyl)-4-methylaniline. 3. In addition to these products azoxy, azo and hydrazo derivatives were formed. 4. Benzyl alcohols and halogenated N-(4'-aminobenzyl)-4-methylanilines were the major microsomal metabolites for all three 2-halogenated 4-methylanilines. 5. Quantification of the metabolite patterns demonstrated an influence of the type of halogen substituent on the rate of microsomal metabolism. The rate of side-chain C-hydroxylation increases in the order 2-fluoro-4-methylaniline < 2-chloro-4-methylaniline < 2-bromo-4-methylaniline. 6. The rate of N-hydroxylation increases from 2-bromo-4-methylaniline < 2-fluoro-4-methylaniline < 2-chloro-4-methylaniline. That 2-chloro-4-methylaniline is N-hydroxylated to a larger extent is in accordance with its greater mutagenicity, twice that of 2-bromo-4-methylaniline.
authors.affiliation: Department of Biochemistry, Agricultural University, Wageningen, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Boeren
authors.forename: B
authors.initials: B
authors.lastname: Tyrakowska
authors.forename: J
authors.initials: J
authors.lastname: Vervoort
authors.forename: E
authors.initials: E
authors.lastname: De Hoffman
authors.forename: K
authors.initials: K
authors.lastname: Teunis
authors.forename: A
authors.initials: A
authors.lastname: van Veldhuizen
authors.forename: I M
authors.initials: IM
authors.lastname: Rietjens
mesh_terms: D000818:Animals; D002849:Chromatography, Gas; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D014052:Toluidines / Q000737:chemistry / Q000378:metabolism*
chemical_list: D014052:Toluidines; D003577:Cytochrome P-450 Enzyme System