Effect of delta-9-tetrahydrocannabinol and theophylline on hepatic microsomal drug metabolizing enzymes.

Theophylline (Th) under in vitro conditions stimulated the activities of rat liver microsomal aniline hydroxylase, N-demethylase and O-demethylase, while delta-9-tetrahydrocannabinol (delta-9-THC) inhibited the activities of these hepatic microsomal drug metabolizing enzymes under similar conditions. delta-9-THC-induced inhibition of hepatic microsomal drug metabolizing enzymes was significantly reduced in the presence of Th. Analysis of Lineweaver-Burk plots showed that Th-induced stimulation of hepatic microsomal drug metabolizing enzymes occurs due to an increase in substrate affinity (1/Km) and of Vmax. delta-9-THC-induced inhibition of N-demethylase and O-demethylase is probably due to competition of the drug with the substrates for a common intermediate in the microsomal electron transport chain. Non-competitive and mixed-type inhibition caused by delta-9-THC on aniline hydroxylation appears to be associated with a non-specific action of delta-9-THC. Blocking of delta-9-THC-induced inhibition or reduction of Th-induced stimulation of hepatic drug metabolizing enzymes with Th or delta-9-THC was due to an increase or decrease in either Vmax, substrate affinity (1/Km) or both with respect to the corresponding Km and Vmax observed with delta-9-THC or Th alone.