1,720,963 research outputs found
Genome-wide transcriptional profiling of two mouse strains with differential susceptibility to doxorubicin-induced cardiotoxicity
No full textDifferential roles of NOS isozymes in cardiotoxicity and mortality following chronic doxorubicin treatment
No full textDifferential roles of nitric oxide synthase isozymes in cardiotoxicity and mortality following chronic doxorubicin treatment in mice
Get PDFThe roles of individual nitric oxide synthases (NOS) in anthracycline-related cardiotoxicity are not completely understood. We investigated the effects of a chronic treatment with doxorubicin (DOX) on knockouts of the individual NOS isozymes and on transgenic mice with myocardial overexpression of eNOS. Fractional shortening (FS) was reduced in untreated homozygous nNOS and iNOS knockouts as well as in eNOS transgenics. DOX-induced FS decrease in wild-type mice was attenuated only in eNOS knockouts, which were found to overexpress nNOS. No worsening of contractility was observed in DOX-treated eNOS transgenics and iNOS knockouts. Although the surviving DOX-treated nNOS knockouts exhibited no further impairment in contractility, most (70%) animals died within 7 weeks after treatment onset. In comparison to untreated wild-type hearts, the nitric oxide (NO) level was lower in hearts from DOX-treated wild-type mice and in all three untreated knockouts. DOX treatment had no effect on NO in the knockouts. These data indicate differential roles of the individual NOS in DOX-induced cardiotoxicity. Protection against DOX effects conferred by eNOS deletion may be mediated by a compensatory overexpression of nNOS. NOS inhibition-based prevention of anthracycline-induced cardiotoxicity should be eNOS-selective, simultaneously avoiding inhibiting nNOS
The reduction of nevirapine-driven HIV mutations by carbamazepine is modulated by CYP3A activity
No full textCarbonyl reductase 1 is a predominant doxorubicin reductase in the human liver
No full textA first step in the enzymatic disposition of the antineoplastic drug doxorubicin (DOX) is the reduction to doxorubicinol (DOX-OL). Because DOX-OL is less antineoplastic but more cardiotoxic than the parent compound, the individual rate of this reaction may affect the antitumor effect and the risk of DOX-induced heart failure. Using purified enzymes and human tissues we determined enzymes generating DOX-OL and interindividual differences in their activities. Human tissues express at least two DOX-reducing enzymes. High-clearance organs (kidney, liver, and the gastrointestinal tract) express an enzyme with an apparent K-m of similar to 140 mu M. Of six enzymes found to reduce DOX, K-m values in this range are exhibited by carbonyl reductase 1 (CBR1) and aldo-keto reductase (AKR) 1C3. CBR1 is expressed in these three organs at higher levels than AKR1C3, whereas AKR1C3 has higher catalytic efficiency
The reduction of nevirapine-driven HIV mutations by carbamazepine is modulated by CYP3A activity
No full textMarmoset CYP3A21, a model for human CYP3A4: Protein expression and functional characterization of the promoter
No full textDue to its small size and the relative evolutionary proximity, the marmoset has been proposed as a model for studies of human drug interactions and metabolism. The current study investigated the expression and regulation of marmoset CYP3A using mass spectrometry and reporter gene techniques. Expression levels of hepatic marmoset CYP3A protein range from 51 to 123 pmolmg(-1) total protein (mean 85.2 pmolmg(-1), n=10) and CYP3A21 is the dominant hepatic CYP3A protein in marmosets. The sequence similarity between human CYP3A4 and CYP3A21 across the first 7.5 kb of the cloned CYP3A21 promoter is 88% within the xenobiotic-responsive enhancer module (XREM) and the proximal promoter. Both regulatory modules confer transcriptional activation of CYP3A21-luciferase reporter gene constructs cotransfected with hPXR in intestinal LS174T cells. The pronounced response to rifampin and the moderate response to dexamethasone were similar to those observed with CYP3A4. Taken collectively, these data establish substantial similarities in expression and gene regulation between marmoset CYP3A21 and human CYP3A4. CYP3A21 may be an equivalent of CYP3A4 in New World monkeys, consistent with the phylogenetic relationship between these genes. The marmoset, therefore, appears to be a suitable in vivo model to study CYP3A4 function and regulation
Reduction of nevirapine-driven HIV mutations by carbamazepine is modulated by CYP3A activity
No full textItem does not contain fulltextOBJECTIVES: The reduction in mother-to-child transmission of HIV-1 by single-dose nevirapine given at birth onset is achieved at the expense of de novo HIV-1 resistance mutations. In the VITA1 study, single-dose carbamazepine accelerated nevirapine elimination, but the accompanying trend towards fewer de novo HIV-1 mutations was statistically non-significant. METHODS: We investigated if the effect of carbamazepine was confounded by the individual variability in nevirapine metabolism and transport. RESULTS: Nine of 34 (26%) single-dose nevirapine-treated women had one or more nevirapine-associated resistance mutations, compared with 3 of 34 (9%) in the single-dose nevirapine/carbamazepine arm. The genetic polymorphisms in CYP2B6 and MRP7 affected neither nevirapine kinetics nor the development of HIV-1 resistance. In contrast, the reduction in HIV-1 mutations by single-dose carbamazepine reached statistical significance at P = 0.04 with an OR of 0.1 (95% CI 0.01-0.90) upon consideration of CYP3A activity, defined as the ratio of 4beta-hydroxycholesterol to cholesterol, and it was more likely in women with higher CYP3A activity. These findings were in agreement with CYP3A induction in carbamazepine-treated patients. Likewise, carbamazepine induced CYP3A4, but not CYP2B6, in vitro when combined with nevirapine. CONCLUSIONS: The induction of nevirapine elimination reduces HIV-1 resistance mutations, but this effect is modulated by individual CYP3A activity. The study suggests that CYP3A4 activity could be monitored using an endogenous marker and, if needed, boosted to improve clinical endpoints
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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