Activated Hepatic Nuclear Factor-κB in Experimental Colitis Regulates CYP2A5 and Metronidazole Disposition.

Systemic exposure of metronidazole is increased in patients with inflammatory bowel diseases (IBDs), while the underlying mechanism remains unknown. Here, we aim to decipher the mechanisms by which experimental colitis regulates metronidazole disposition in mice. We first confirmed that the systemic exposure of metronidazole was elevated in dextran sulfate sodium (DSS)-induced experimental colitis. Hepatic microsomal incubation with metronidazole revealed that the production rate of 2-hydroxymetronidazole was inhibited, suggestive of a diminished hydroxylation reaction upon colitis. Remarkably, the hydroxylation reaction of metronidazole was selectively catalyzed by CYP2A5, which was downregulated in the liver of colitis mice. In addition, hepatic nuclear factor (NF)-κB (a prototypical and critical signaling pathway in inflammation) was activated in colitis mice. Luciferase reporter and chromatin immunoprecipitation assay indicated that NF-κB downregulated Cyp2a5 transcription through binding to an NF-κB binding site (-1711 to -1720 bp) in the promoter. We further verified that the regulatory effects of colitis on CYP2A5 depended on the disease itself rather than the DSS compound. First, one-day administration of DSS did not alter mRNA and protein levels of CYP2A5. Moreover, CYP2A5 was suppressed in the Il-10-/- spontaneously developing colitis model. Furthermore, Cyp2a5 expression was downregulated in both groups of mice with modest or severe colitis, whereas the expression change was much more significant in severe colitis as compared to modest colitis. Altogether, activated hepatic NF-κB in experimental colitis regulates CYP2A5 and metronidazole disposition, revealing the mechanism of pharmacokinetic instability under IBDs, and providing a theoretical foundation for rational drug use in the future.

Prevalence of potentially severe drug-drug interactions in ambulatory patients with dyslipidaemia receiving HMG-CoA reductase inhibitor therapy.

BACKGROUND: Drug-drug interactions (DDIs) are a well known risk factor for adverse drug reactions. HMG-CoA reductase inhibitors ('statins') are a cornerstone in the treatment of dyslipidaemia and patients with dyslipidaemia are concomitantly treated with a variety of additional drugs. Since DDIs are associated with adverse reactions, we performed a cross-sectional study to assess the prevalence of potentially critical drug-drug and drug-statin interactions in an outpatient adult population with dyslipidaemia. METHODS: Data from patients with dyslipidaemia treated with a statin were collected from 242 practitioners from different parts of Switzerland. The medication list was screened for potentially harmful DDIs with statins or other drugs using an interactive electronic drug interaction program. RESULTS: We included 2742 ambulatory statin-treated patients (mean age +/- SD 65.1 +/- 11.1 years; 61.6% males) with (mean +/- SD) 3.2 +/- 1.6 diagnoses and 4.9 +/- 2.4 drugs prescribed. Of those, 190 patients (6.9%) had a total of 198 potentially harmful drug-statin interactions. Interacting drugs were fibrates or nicotinic acid (9.5% of patients with drug-statin interactions), cytochrome P450 (CYP) 3A4 inhibitors (70.5%), digoxin (22.6%) or ciclosporin (cyclosporine) [1.6%]. The proportion of patients with a potential drug-statin interaction was 12.1% for simvastatin, 10.0% for atorvastatin, 3.8% for fluvastatin and 0.3% for pravastatin. Additionally, the program identified 393 potentially critical non-statin DDIs in 288 patients. CONCLUSIONS: CYP3A4 inhibitors are the most frequent cause of potential drug interactions with statins. As the risk for developing rhabdomyolysis is increased in patients with drug-statin interactions, clinicians should be aware of the most frequently observed drug-statin interactions and how these interactions can be avoided.

[Damage factors in tobacco and tobacco smoke]. / Schadstoffe im Tabak und Tabakrauch.

In the last 30 years the production and consumption of cigarettes are increasing permanently. Till now more than 2200 noxious substances have been detected in the smoke of cigarettes. The origin and the synthesis of selected groups of these compounds and their distribution on main- and on sidestream smoke are described, furthermore the possibilities for estimation and control of nicotine abuse are reviewed. The incorporation of noxious substances of tobacco smoke result in a damage of clearance mechanisms of the lung and a change of loading by drugs and other metabolisable noxious substances, because the biotransformation processes are influenced by tobacco smoke. In this connection the importance of aryl-hydrocarbon-hydroxylase is discussed.

Cutaneous chemical carcinogenesis: past, present, and future.

Skin tumors chemically induced in mice have provided an important experimental model for studying carcinogenesis and for bioassaying carcinogenic agents. The information obtained from this model suggests that the events leading to tumor formation can be divided into at least two stages, initiation and promotion. A single small dose of carinogen produces initiation which appears to be irreversible. These initiating agents may have to be metabolically activated and can interact with cellular macromolecules. The extent to which they bind to DNA correlates well with their carcinogenicity. Increased DNA replication at the time of or during the first day after these agents have been applied appears to enhance carcinogenesis. Unlike initiation, promotion appears to be reversible and the promoting agents must be applied repeatedly before tumors are formed. Promoters interact with membranes, stimulate and alter genetic expression, and increase the rate of cell proliferation. The knowledge gained from these studies in mouse skin has immeasurably helped the entire field of chemical carcinogenesis. But efforts to determine the cellular and molecular mechanisms involved in the carcinogenic process, particularly in the skin, have been hampered by the difficulties of working on whole animals and by the special problems associated with the biologic and biochemical methods required for this target organ. Such problems, however, can be solved by the use of cell cultures of mouse epidermis which can metabolize and bind carcinogens just as is done in vivo. The fact that epidermal cells in vitro proliferate synchronously should facilitate the study of the relation between the cell cycle and carcinogenesis. These cells repair chemically induced DNA damage by at least two mechanisms, excision repair and base-specific repair. When epidermal cells in vitro are exposed to promoting agents, a proliferative response analogous to that in vivo is elicited, apparently mediated through control of polyamine metabolism. Neoplastic transformation has been induced in these cultures by known skin carcinogens.