Induction of alkoxyresorufin O-dealkylases, epoxide hydrolase, and liver weight gain: correlation with liver tumor-promoting potential in a series of barbiturates.

Abstract

The effects of a series of barbiturates, of known and varying liver tumor-promoting ability, on several short-term endpoints including liver weight and liver-to-body weight ratio increases and induction of cytochromes(s) P-450 and epoxide hydrolase activities were examined. Male F344 rats (3 months of age) were administered barbiturates in the drinking water for 12 days. At the end of the treatment period they were killed, body and liver weights were taken, microsomal p-nitroanisole O-demethylation and epoxide hydration, and liver S-9 O-dealkylation of ethoxy-, pentoxy- and benzyloxyresorufin were measured. The latter two substrates have been shown to be preferentially metabolized by the major phenobarbital-inducible form of cytochrome(s) P-450 (P-450b), and were employed since they offered a means of differentiating more clearly varying levels of P-450 induction. Exposure to sodium barbital (SB) and sodium phenobarbital (PB) resulted in significant increases in liver weight and liver-to-body weight ratios. Induction of cytochrome(s) P-450 and epoxide hydrolase activities by the various barbiturates depended on the functional groups on C5. When ranked in terms of decreasing induction potency, the following order was obtained for each enzyme activity quantitated: PB, SB, sodium pentobarbital, amobarbital, hexobarbital and the C5-unsubstituted parent compound (barbituric acid). Thus, the barbiturates were found to exhibit a spectrum of induction potencies, with PB and SB, the most potent liver tumor promoters, yielding the greatest degree of liver weight increase and induction of cytochrome(s) P-450 and epoxide hydrolase activities.