Species differences in induction of hepatic enzymes by BM 17.0744, an activator of peroxisome proliferator-activated receptor alpha (PPAR alpha)

BM 17.0744, a new anti-diabetic and lipid-lowering agent, leads also to str ong hepatomegaly and carnitine acetyl transferase (CAT) increase in the liv er of rats, a phenomenon known from fibrates. For information on the releva nce of changes in liver of rats to other species, we investigated the effec ts of BM 17.0744 on lipids and selected marker enzymes related to beta-oxid ation in rats, dogs and guinea-pigs, so-called high and low responders to p eroxisome proliferators. To examine selectivity other enzymes were also det ermined, e.g, esterase, urate oxidase (UOX) and cytochrome c oxidase (CYT.C .OX.). Lowering of triglycerides and cholesterol in blood serum and/or live r was observed in pharmacological dose range in the three species tested. I n dogs and guinea-pigs, liver and kidney weights were unaffected even in do gs in medium and high dose groups with high systemic exposure and severe to xicity. In male Sprague-Dawley rats treatment with 1.5, 3, 6 and 12.5 mg/kg per day BM 17.0744 selectively elevated the activities of CAT and acyl-CoA oxidase (AOX) by less than or equal to 200 and 20-fold, respectively. Admi nistration of BM 17.0744 to Beagle dogs (1.5, 4, 12 mg/kg per day) and guin ea-pigs (3 and 12 mg/kg per day) enhanced the activities of CAT and AOX dos e-dependently by a factor of two to three only. Immunoblotting revealed a d rug-specific enhancement of the amount of beta-oxidation enzymes in rats, w hich is in accord with the rapid and coordinated transcriptional activation shown in Northern dot blot analysis. Nuclear run-on assays demostrated a r eal transcriptional activation. BM 17.0744 activates peroxisome proliferato r-activated receptor alpha (PPAR alpha), which could be shown by transactiv ation assays. The stimulation of PPAR alpha by BM 17.0744 was stronger than that of the known ligands WY 14.643 and ETYA. Activation of PPAR gamma can be excluded. Taken collectively, the data demonstrate an enhancement of th e beta-oxidation system by BM 17.0744 paralleled by lipid-lowering in all s pecies investigated. The activation of the nuclear factor PPAR alpha may ex plain the changes in liver and the metabolic effects on the molecular level . The lack of an increase in liver and kidney weights and the relatively mo derate enhancement of activities of beta-oxidation-related enzymes in dogs and guinea-pigs indicate that the excessive response observed in rats is no t applicable to other, predominantly non-rodent, species. On the basis of t hese data and the experience with fibrates a specific risk for humans is no t expected.