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Microsomes were prepared from human livers obtained from renal donors of various ages and both sexes. Their drug-metabolizing capacity was measured and compared to that of rat liver microsomes. The following parameters were investigated: cytochrome P-450, cytochrome bs, NADPH -cytochrome c reductase, epoxide hydrolase, aryl hydrocarbon hydroxylase, benzphetamine N-demethylase, p-nitroanisole-0-demethylase, ethoxycoumarin-0-deethylase, steroid-16a-hydroxylase. In addition, the metabolism of benzo(a)pyrene, progesterone, pregnenolone, testosterone, dehydroepiandrosterone and estradiol was studied in detail in vitro. The inhibitory effect of metyrapone and a-naphthoflavone on 7-ethoxycoumarin-0-deethylase was measured. The microsomal proteins of both species were separated by polyacrylamide gel electrophoresis in the presence of dodecyl sulfate.The following conclusions were drawn from the results obtained. Human liver microsomes can be stored under optimal conditions for the measurement of a large variety of enzymic activities. Human liver microsomes are able to metabolize the various xenobiotics used as substrates with a rate similar to that of female rat liver microsomes. No sex-linked difference in enzymic activity was observed in human microsomes. Significant differences in benzo(a)pyrene and steroid metabolism were registered when human and rat liver microsomes were compared. The monooxygenase activities, the sensitivity to in v i m a-naphthoflavone and metyrapone, the results of steroid metabolism, and slab gel electrophoresis are strong indications for multiplicity of human liver cytochrome P-450.Without appropriate means, living organisms would never be able to eliminate from their systems the lipophilic compounds which are either produced by their own metabolism (i.e. steroid hormones, fatty acids, prostaglandins), or are accidentally or voluntarily absorbed from their environment (i.e. food additives, drugs, pesticides, pollutants . . .). Living organisms have thus developed a number of enzymic systems which transform these substances into more polar and therefore more hydrophilic metabolites which can be easily excreted via the urine or feces.The first step in these metabolic transformations is usually catalyzed by (cytochrome P-450)-dependent monooxygenases. These microsomal multienzyme complexes oxidize a great variety of endogenous as well as exogenous substrates. Their biochemical and biological properties have been extensively studied in laboratory animals [l -41. The different types of cytochrome P-450 are characterized by their substrate specificity. Their qualitative and quantitative proportions in a given tissue vary largely as a function of physiological, pharmacological and pathological parameters [2,3,5].Trivia! Numes. r-Naphthoflavone, 7,8-benzoflavone; rnetyrapone, 2-methyl-1,2-di-3-pyridyl-l -propanone; progesterone, pregn-4-en-3,20-dione; pregnenolone, 3p-hydroxypregn-5-en-20-one; testosterone, androst-4-en-I7f1'-01-3-one; dehydroepiandrosterone, 3p-hydroxyandrost-5-en-1 7-one; estradiol...

Anthracycline drugs are widely used for the treatment of solid tumors and leukemia, but the molecular basis of their biological eect is still poorly understood. In the HCT 116 colon carcinoma cell line, which retains a wildtype inducible p53 gene, we show that the anthracycline daunomycin is a potent inducer of p53 and NF-kB transcription factors. Nuclear accumulation of p53 protein occurred because of increased protein stability and enhanced gene expression. In addition, daunomycin induced the p53 promoter through the binding of p50/p65 NF-kB heterodimers to the kB site in the p53 promoter. Under our conditions, the free radical scavengers NAC and PDTC were not able to block NF-kB activation or p53 induction, indicating that reactive oxygen intermediates were not involved in the cellular response to daunomycin stimulation. Overexpression of a stable unresponsive IkBa mutant in HCT116 cells resulted in a complete inhibition of the NF-kB activation but only a partial impairment of the p53 protein accumulation induced by daunomycin. We conclude that the p53-activating signal generated by daunomycin is partially regulated by NF-kB.

Death rattle is a frequent symptom (25%-50%) in the terminal stage of life, but there is neither standardized treatment nor prospective investigation performed on the effectiveness of anticholinergic drugs. The aim of the present study was to investigate the effectiveness of three different anticholinergic drugs in the treatment of death rattle in the terminal stage of life. Terminal patients who developed death rattle were randomly assigned 0.5mg atropine, 20mg hyoscine butylbromide, or 0.25mg scopolamine. Each treatment was initiated with a subcutaneous bolus, which was followed by continuous administration of the same drug. The intensity of death rattle and side effects were prospectively scored at different time points. Three hundred and thirty-three eligible patients were randomized to atropine, hyoscine butylbromide, or scopolamine after informed consent from the patient or the appointed representative. For the three drugs, death rattle decreased to a nondisturbing intensity or disappeared after one hour in 42%, 42%, and 37% of cases, respectively (P=0.72). Further, effectiveness improved over time without significant differences among the treatment groups (effectiveness at 24 hours was 76%, 60%, and 68%, respectively). In an analysis on the three groups together, treatment was more effective when started at a lower initial rattle intensity; median survival after start of therapy was 23.9 hours. These data suggest that there are no significant differences in effectiveness or survival time among atropine, hyoscine butylbromide, and scopolamine in the treatment of death rattle.