Anti-inflammatory agents and inducibility of hepatic drug metabolism

Two rat liver cytosolic aldehyde dehydrogenases, ALDH1 and ALDH3c, are of p articular interest because they are inducible by different classes of xenob iotics. ALDH1 is mainly increased by phenobarbital-type inducers; polycycli c aromatic hydrocarbons (PAHs), such as 3- methylcholanthrene (3MC), increa se ALDH3c enzyme activity in all rat species currently tested. In addition, ALDH3c has been found to reflect the subfamily CYP1A of cytochrome P- 450, as well as other enzymes functionally related to the aryl hydrocarbon rece ptor (the (n)Ah-receptor enzyme battery(n)), which is activated by the same type of inducers. In the present study we investigated whether the inducti on of ALDH3c might be connected with a chemically produced aseptic inflamma tion of the hepatocyte. To answer this question, we examined the relationsh ip between the induction of ALDH3c by 3MC and the arachidonic acid cascade. Different non-steroid anti-inflammatory drugs (NSAIDs) were tested in comb ination with 3MC and in post-treatment. The 3MC-induced ALDH3c activity was significantly diminished by the co-administered anti-inflammatory agents. Two microsomal enzyme activities (ethoxyresorufin-O-deethylase, EROD; aryl- hydrocarbon-hydroxylase, AHH) were also decreased. Similar results were obt ained with NSAIDs administered to animals pre- treated with 3MC, as far as the ALDH3c activity was concerned, but not for the microsomal enzyme activi ty (EROD and AHH). In conclusion, the induction of ALDH3c, after PAH treatm ent, may be related to an aseptic inflammation of the hepatocytes. This eff ect is reduced by commonly used steroid and non-steroid anti- inflammatory drugs, and although the mechanism of inhibition has not yet been elucidated , it appears likely that ALDH3c and CYP1A activities are associated with th e "acute phase" response.