Abstract

Human liver slices, in vitro, were used to establish whether lidocaine (LIDO) can be converted by human liver tissue to 2,6-xylidine (XYL), a compound shown to be carcinogenic in rodents. XYL was identified by GC/MS as a major metabolite in human liver slices from five individual donors after incubation with either LIDO (100 microM) or its deethylated metabolite, monoethylglycinexylidide (MEGX; 100 microM). Similar media XYL concentrations (9.8 microM +/- 2.1 SD and 7.9 microM +/- 2.1 SD) were achieved after either LIDO or MEGX incubation for 4 hr, respectively. With LIDO, the mean media XYL to MEGX ratios were 1.1 at 1-hr and 1.0 at 4-hr incubation times. In contrast, when LIDO (> 500 microM) was incubated with human liver microsomes for 1 hr, the XYL to MEGX ratio was approximately 0.01. No XYL was detected when LIDO (100 microM) was incubated with either human liver S9 fractions or whole liver homogenates. These results suggest that the enzyme primarily responsible for hydrolysis of LIDO may be labile in subcellular fractions. Kinetic analysis of the data suggests that XYL can be produced from either LIDO directly, or sequentially through MEGX. Although these metabolic data are helpful in addressing issues of LIDO toxicity, the overall risk assessment for LIDO is determined in large part by other factors, including the relative rates of activation to other potentially toxic species such as 4-HO-2,6-XYL as well as inactivation by detoxification pathways. The results presented emphasize the important role human liver slices can play in drug metabolism studies.