Influence of substrate concentration on the phase I and phase II metabolism of 4-methoxybiphenyl by rat isolated hepatocytes

Abstract

1. The metabolism of 4-methoxybiphenyl to 4-hydroxybiphenyl and its sulphate and glucuronic acid conjugates has been studied in rat isolated hepatocytes at various concentrations of 4-methoxybiphenyl.

2. The proportions of metabolites produced remained constant at concentrations of 4-methoxybiphenyl less than 25–50 μM, but at higher concentrations the pattern of metabolism changed, there being proportionally more unconjugated 4-hydroxybiphenyl and its glucuronide, and less 4-hydroxybiphenyl sulphate.

3. The amount of 4-hydroxybiphenyl sulphate produced approached a plateau at the highest level of overall metabolism, whereas the amount of 4-hydroxybiphenyl glucuronide produced was linearly related to the amount of unconjugated 4-hydroxybiphenyl detected.

4. These data are consistent with the view that sulphation acts as a high-affinity, low-capacity pathway, whereas glucuronidation acts as a low-affinity, high-capacity pathway.