title: In vitro and in vivo evaluations of the methaemoglobinaemic potential of xylidine isomers in the rat.
abstract: The objective of the present study was to evaluate the methaemoglobinaemic potential of the six isomers of xylidine (XYL) by two approaches: in vitro, using rat red blood cells and hepatic post-mitochondrial fractions in a two-compartmental dialysis system; and in vivo, following a single oral dose of 4.8 mmol kg(-1) (p.o.) of each of the six XYL isomers. The in vitro experiments showed that all six XYL isomers at 1 mM concentration induced significant methaemoglobinaemia in the presence of active hepatic fractions, whereas non-bioactivated XYL isomers were totally inactive. At lower incubation concentrations (0.3 mM and 0.06 mM), 3,5-XYL was still active, whereas the other isomers were less potent (0.3 mM) or totally ineffective (0.06 mM). The in vivo experiment revealed that all XYL isomers, except 3,5-XYL, did not induce significant methaemoglobinaemia after a single oral dose of 4.8 mmol kg(-1). The maximal percentage of methaemoglobin was 31.3 +/- 1.5 in the 3,5-XYL-treated rats, whereas it never exceeded 3% in all the other treatment groups, indicating that 4.8 mmol kg(-1) (p.o.) is in fact a no-observable-adverse-effect level for these XYL isomers. The quantitative differences between in vivo and in vitro results may have been due to additional bioactivation pathways (N-hydroxylation or ring hydroxylation) mediated by high Km enzymes operative at the high incubation concentrations used in vitro. The results of the present study suggest that 3,5-XYL is likely to be the only active isomer in the Sprague-Dawley rat at low exposure levels.
authors.affiliation: Département de médecine du travail et d'hygiène du milieu, Faculté de médecine, Université de Montréal, Succursale Centre-ville, Québec, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Cauchon
authors.forename: K
authors.initials: K
authors.lastname: Krishnan
mesh_terms: D000284:Administration, Oral; D000814:Aniline Compounds / Q000633:toxicity*; D000818:Animals; D019540:Area Under Curve; D002478:Cells, Cultured; D003956:Dialysis / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008708:Methemoglobinemia / Q000139:chemically induced*; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D000814:Aniline Compounds