Differential effect of pentoxifylline on lipopolysaccharide-induced downregulation of cytochrome p450

• Published in: Biochemical pharmacology 1996-10, Vol.52 (8), p.1195-1200
• Main Authors: Monshouwer, Mario, McLellan, Roman A., Delaporte, Enock, Witkamp, Renger F., van Miert, Adelbert S.J.P.A.M., Renton, Kenneth W.
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cytochrome P-450 CYP1A1 - genetics; Cytochrome P-450 CYP1A1 - metabolism; Cytochrome P-450 CYP1A2 - genetics; Cytochrome P-450 CYP1A2 - metabolism; Cytochrome P-450 CYP2E1 - genetics; Cytochrome P-450 CYP2E1 - metabolism; Cytochrome P-450 Enzyme System - genetics; Cytochrome P-450 Enzyme System - metabolism; cytochrome P450; Down-Regulation - drug effects; downregulation; Immunomodulators; Interferon Inducers - pharmacology; lipopolysaccharide; Lipopolysaccharides - pharmacology; Liver - drug effects; Liver - metabolism; Male; Medical sciences; pentoxifylline; Pentoxifylline - pharmacology; Pharmacology. Drug treatments; Phosphodiesterase Inhibitors - pharmacology; Poly I-C - pharmacology; polylC, tumor necrosis factor; Rats; Rats, Sprague-Dawley; RNA, Messenger - genetics; RNA, Messenger - metabolism; Tumor Necrosis Factor-alpha - biosynthesis; Tumor Necrosis Factor-alpha - genetics
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/0006-2952(96)00468-6

It is now established that inflammatory stimuli such as lipopolysaccharides (LPS) and polyinosinic acid:polycytidylic (polyIC) suppress hepatic expression of cytochrome P450 (P450) genes in rat liver. Previous studies have suggested that LPS- or polyIC-induced downregulation of P450 was due to endogenously released inflammatory cytokines such as tumor necrosis factor-a (TNF-α), interleukin-1, interleukin-6, and interferons (IFNs). To improve our understanding of the role of inflammatory cytokines in mediating P450 depression, we investigated the possibility of preventing P450 downregulation with pentoxifylline. Pentoxifylline has been shown to inhibit LPS-induced TNF-a production by suppression of TNF-a gene expression. The present study shows that in uninduced male rats pentoxifylline selectively prevents the downregulation of microsomal P4501A2 and P4502B caused by LPS. No protective effect of pentoxifylline on the downregulation of P4502E1 and P4503A1/2 was observed. PolylC-induced downregulation of P4501A2, P4502B, P4502E1, and P4503A1/2 was not affected by pentoxifylline. These results suggest that the LPS-induced downregulation of P4501A2 and P4502B is mediated to a large extent by TNF-α. Other cytokines might be involved in the suppression of P4502E1 and P4503A1/2. The fact that polylC-induced downregulation is not protected by pentoxifylline is further evidence that this agent acts via a selective induction of IFNs.