In vitro and in vivo evaluations of the methaemoglobinaemic potential of xylidine isomers in the rat

✍ Scribed by Denis Cauchon; Kannan Krishnan

• Publisher: John Wiley and Sons
• Year: 1997
• Tongue: English
• Weight: 107 KB
• Volume: 17
• Category: Article
• ISSN: 0260-437X
• DOI: 10.1002/(sici)1099-1263(199711/12)17:6<397::aid-jat458>3.0.co;2-v

✦ Synopsis

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.