Received for publication July 13, 2005.
Revised September 28, 2005.
Accepted for publication September 29, 2005.

Modulation of CYP1A2 and CYP3A6 catalytic activities by serum from rabbits with a turpentine-induced inflammatory reaction and IL-6

Abstract

Inflammatory reactions reduce the activity of cytochrome P450 (P450) isoforms. The aim of the study was to determine the mechanisms underlying the decrease in CYP1A2 and CYP3A6 catalytic activities produced by serum from rabbits with a turpentine-induced inflammatory reaction (S_TIIR) and IL-6. S_TIIR and IL-6 were incubated with cultured primary hepatocytes from control rabbits (H_CONT), and from rabbits with a turpentine-induced inflammatory reaction (H_TIIR) in absence or presence of pyrrolidine dithiocarbamate (PDTC), an antioxidant and inhibitor of NF-kappaB transcription, PD98059, an inhibitor of extracellular signal-related kinase (Erk1/2), SB203580, an inhibitor of p38MAPK, N-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase-2 (NOS2), the combination of PDTC, PD98059 and SB203580, and genistein, an inhibitor of Janus-associated protein tyrosine kinase (JAK). After 4 and 24 h of incubation of H_CONT with S_TIIR and IL-6, CYP1A2 activity was reduced without changes in expression; the reduction in activity was partially prevented by the inhibition of JAK, Erk1/2, and NOS2. In H_CONT, S_TIIR and IL-6 did not affect CYP3A6 activity; however, PDTC reduced CYP3A6 activity by 40 and 80% after 4 and 24 h of incubation. In H_TIIR, S_TIIR and IL-6 reduced both CYP1A2 and CYP3A6 activities; this decrease is partially prevented by inhibitors of protein tyrosine kinases, Erk1/2, and NOS2. In H_TIIR, SB203580 increased CYP3A6 activity dose-dependently without changes in protein expression. These results show that the signal transduction pathways mediating the decrease in CYP1A2 and 3A6 activity, produced by S_TIIR and IL-6, involve JAK, Erk1/2 and NOS2.

Key words: CYP inhibition, CYP1A, CYP3A, cytochrome P450 regulation, interleukins, isolated hepatocytes, nitric oxide synthase, oxygen radicals