Putrescine decreases cytochrome P450 3A4 levels during liver regeneration in the rat

Abstract

Background/Aims: The mechanism by which many cytochrome P450 (CYP) isozymes decrease during liver regeneration is unclear. Peptides and growth factors are thought to be involved. Putrescine, the first polyamine synthesised by ornithine decarboxylase, peaks early following partial hepatectomy and is known to play an essential role in hepatic regeneration. Gamma amino butyric acid was reported as a physiologic inhibitor of ornithine decarboxylase. In this work we studied the possible involvement of putrescine in the CYP reduction during liver regeneration. Methods: Hepatectomised, putrescine-treated sham, and GABA-treated hepatectomised rats were used throughout. Total hepatic cytochrome P450, o-dealkylase activities (CYP1A1 and CYP2B1/2), nifedipine oxidase activity (CYP3A4), and Western blot assays of their respective apoproteins were analysed in liver microsomes. Putrescine levels in hepatic tissue were also measured. Results: Partial hepatectomy and putrescine treatment induced a significant diminution in total CYP (50% and 30% of sham-operated rats, respectively). Gamma amino butyric acid treatment prevented this decrease in partially hepatectomised rats. Nifedipine oxidase activity of partially hepatectomised and putresciine-treated rats significantly decreased to 43% and 60% of that in sham-operated rats, respectively. Again, gamma amino butyric acid prevented the diminution in partially hepatectomised rats. No significant changes were observed in o-dealkylase activities. Conclusions: These results show that inducible CYP1A1 and CYP2B1/2, which are important in carcinogen metabolisation, are preserved after partial hepatectomy. However, constitutive CYP3A4, which represents 50% of total CYP and metabolises drugs like nifedipine, warfarin, acetaminophen, cyclosporin and FK-506, is reduced during liver regeneration. Our experiments suggest that endogenous putrescine is, at least, partly responsible for this decrease.