Depression of constitutive murine cytochromes P450 by staphylococcal enterotoxin B.

Most in vivo studies demonstrating decreased activities of hepatic cytochromes P450 with inflammation have used Gram-negative bacterial lipopolysaccharide (LPS) as the inflammatory stimulant. But products of Gram-positive bacteria, such as staphylococcal enterotoxin B (SEB), also stimulate inflammatory mediators, albeit with a different pattern than LPS. Therefore, effects of SEB on the regulation of murine constitutive P450s were determined in this study and compared with those of LPS. LPS-responsive C3H/HeN and LPS-unresponsive C3H/HeJ mice were injected with either LPS (0.5 mg/kg) or SEB (0.66 to 6.6 mg/kg), and hepatic cytochromes P450 and serum tumor necrosis factor-alpha, interleukin-6, nitrate/nitrite, and serum amyloid A concentrations were determined up to 24 hr. HeJ mice were generally less responsive than HeN mice to both stimuli, with lower cytokine, nitrate/nitrite, and serum amyloid A responses. However, in both mouse strains SEB caused more prolonged cytokine, higher nitrate/nitrite, and lower serum amyloid A concentrations than LPS. Despite these differences, in HeN mice, after both SEB and LPS administration, total P450 concentrations were equally depressed by 40%. Both SEB and LPS depressed CYP1A1 and 1A2 microsomal protein concentrations by 45 and 30%, respectively; CYP2E1 by 64%; and CYP3A by 70%. There was comparable inhibition of enzymatic activities. In HeJ mice, SEB was only slightly more effective in depressing P450s than LPS, as might be expected. These data showed that the Gram-positive bacterial inflammatory stimulant SEB caused effects on murine hepatic cytochromes P450 similar to those of LPS, even though the pattern of inflammatory mediators induced after SEB exposure was different.

The effect of endotoxin administration on the pharmacokinetics of chlorzoxazone in humans.

OBJECTIVE: Inflammation induced by Escherichia coli lipopolysaccharide alters the clearance of several hepatically eliminated drugs. Extensive rat liver research has shown CYP2E1 down-regulation after lipopolysaccharide administration. To further investigate this phenomenon in humans, lipopolysaccharide was administered to healthy male volunteers and chlorzoxazone was used as a CYP2E1 probe drug. METHODS: Twelve healthy men were given 500 mg oral chlorzoxazone after two daily lipopolysaccharide doses (20 endotoxin units/kg/day) and again after administration of saline solution in this balanced crossover study. Serum and urine chlorzoxazone and 6-hydroxychlorzoxazone were quantified, as well as cytokine and C-reactive protein levels. RESULTS: Lipopolysaccharide produced the expected induction of the acute-phase response shown by elevations in tumor necrosis factor, interleukin-6, C-reactive protein, and temperature. Lipopolysaccharide treatment failed to produce a significant change in the chlorzoxazone oral clearance (4.4 +/- 0.9 mL/min/kg for lipopolysaccharide versus 4.2 +/- 1.4 mL/min/kg for control) or the 6-hydroxychlorzoxazone formation clearance (2.8 +/- 0.65 mL/min/kg for lipopolysaccharide versus 2.5 +/- 0.9 mL/min/kg for control). The high intersubject variabilities in oral clearance and formation clearance were not accounted for by changes in protein binding, cytokine, or C-reactive protein values. In contrast, a significant increase in the 6-hydroxychlorzoxazone glucuronide renal clearance was observed (7.5 +/- 1.37 mL/min/kg for lipopolysaccharide versus 6.1 +/- 1.7 mL/min/kg for control). CONCLUSIONS: This study showed that the inflammatory response to lipopolysaccharide (20 endotoxin units/kg/day for 2 days) in humans does not consistently alter chlorzoxazone hepatic metabolism. However, the significant increase in renal clearance of the glucuronidated metabolite suggests that renal tubular secretion may be increased in humans with acute endotoxemia.

Endotoxin depresses hepatic cytochrome P450-mediated drug metabolism in women.

AIMS: In men, the inflammatory response to intravenous endotoxin depresses apparent oral clearances of antipyrine, hexobarbitone, and theophylline. The aim of this study was to investigate whether there might be gender differences in the regulation of hepatic cytochromes P450. METHODS: Experiments were carried out in seven healthy women volunteers (ages 19-51, median 22 years). Each woman received a cocktail of the three drugs on two occasions, once after a saline injection and again after endotoxin. RESULTS: Endotoxin injections, but not saline, caused the expected physiologic responses of inflammation including fever and increases in circulating tumor necrosis factor-alpha, interleukin-6, and C-reactive protein. When compared with the saline control studies, endotoxin significantly decreased clearances of all probes: antipyrine, 31% (95%CI 21%-41%); hexobarbitone, 20% (95%CI 10-31%); and theophylline, 20% (95%CI 10%-30%). The decreases were comparable with those found in the men previously studied (35%, 27%, and 22%, respectively). CONCLUSIONS: These data show that endotoxin-induced inflammation decreases hepatic cytochrome P450-mediated metabolism of selected probe drugs in women as it does in men.

[Functional criteria for the differentiation of leukemic cells. II. The fungicidal activity of the blast cells from patients with acute monoblastic leukemia]. / Funktsionalni kriterii za diferentsiatsiiata na levkozni kletki. II. Fungitsidna aktivnost na blastni kletki ot bolni s ostra monoblastna lekoza.

The studies in the present work are a continuation of the previous studies of the author's on the functional activity of leukosis cells and discuss their fungicidal activity versus Candida albicans. Blast cells from 22 patients with various clinical-morphological forms of acute leukosis were studied. It has been concluded from the results obtained that leukosis cells of monoblast type in acute myelomonoblast (M4) and monoblast (M5) leukosis are able to lyse Candida albicans, the value of their fungicidal activity being lower than that of mature monocytes from peripheral blood of healthy subjects. The fungicidal activity is observed in leukosis cells from patients with promyelocyte (M3) leukosis. The authors propose the fungicidal activity of leukosis cells to be used as an additional, functional criterium in the differentiation of their type.

Biosynthesis of lipid-linked oligosaccharides by microsomes from virus induced Hepatoma MC-29. Dependence of some glycosyl transferases on dolichyl phosphates of different chain length.

Dolichyl phosphates of various chain length ranging from 7 to 22 isoprene units were tested as lipid acceptors in transglycosylation reactions in chicken liver and Hepatoma MC-29. In the presence of exogenous dolichyl phosphate mixture (18 and 19 isoprene units) the synthesis of dolichyl pyrophosphate N-acetylglucosamine and dolichyl phosphate mannose increased 3 times both in the liver and Hepatoma MC-29, while the formation of dolichyl phosphate glucose was 4 fold higher in the liver and 6-fold higher in Hepatoma MC-29. In liver microsomes the maximum rate of the stimulation of glycosylation was achieved by exogenous dolichyl phosphates, containing 18 and 19 isoprene units, while glycosyl transferases in microsomes from Hepatoma MC-29 did not show any structural requirements to the chain length of dolichyl phosphates.

[Clinical, morphological, cytochemical and ultrastructural studies of a female patient with basophilic leukemia]. / Kliniko-morfologichni, tsitokhimichni i ultrastrukturni prouchvaniia pri bolna s bazofilna levkoza.

The morphological, cytochemical and ultrastructural characteristics of basophilic cells in patients with chronic myeloleukosis were studied. The basophilic elements, dynamically followed up, from all phases of maturation, represented from 48 to 83 per cent of the cellular population in the peripheral blood and marrow. The cytochemical and ultrastructural investigations confirmed their belonging to the basophilic line. Certain changes were found, being an evidence of disorders in the maturation and metabolism of the cells. The high basophilic index, combined with a low neurophilic one, suggest the participation of the basophilic line in the leukosis process. On the base of the results obtained, the conception of the existence of basophilic leukosis is admitted.