Swinholide J, a Potent Cytotoxin from the Marine Sponge Theonella swinhoei

In our ongoing search for new pharmacologically active leads from Solomon organisms, we have examined the sponge Theonella swinhoei. Herein we report the isolation and structure elucidation of swinholide A (1) and one new macrolide, swinholide J (2). Swinholide J is an unprecedented asymmetric 44-membered dilactone with an epoxide functionality in half of the molecule. The structural determination was based on extensive interpretation of high-field NMR spectra and HRESIMS data. Swinholide J displayed potent in vitro cytotoxicity against KB cells (human nasopharynx cancer) with an IC50 value of 6 nM

Distribution of cytochromes P-450, cytochrome b5, and nadph-cytochrome P-450 reductase in an entire human liver

In rat liver there appear to be significant differences between lobes in the concentration of individual cytochrome P-450 isozymes (Sumner and Lodola, Biochem Pharmacol 36: 391-393, 1987). Because studies in patients often rely on small pieces of liver obtained from diverse anatomical locations, it seemed important to determine if the cytochromes P-450 were also heterogeneously distributed in human liver. Accordingly, tissue was obtained from ten different locations in a single human liver including those most commonly biopsied by percutaneous needles, and by surgeons during laparotomy. The differences observed between locations in the microsomal concentrations of carbon monoxide-binding protein (total cytochrome P-450), cytochrome b5, and NADPH-cytochrome P-450 reductase appeared to be small and were not statistically significant. Likewise, no significant differences were observed between locations in the specific content of HLp, HLp3, HLj, HLx or P450MP. However, the specific concentrations of HLd varied almost 2-fold between the microsomes and this was statistically significant in some cases (P < 0.05). Our results suggest that, in human livers, regional differences in the content of cytochromes P-450 are generally small but may be significant for some isozymes. With the exception of HLd, tissue obtained by percutaneous or surgical liver biopsies is probably representative of the entire organ with regard to the enzymes assayed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28744/1/0000574.pd

Contact-facilitated drug delivery with Sn2 lipase labile prodrugs optimize targeted lipid nanoparticle drug delivery

Sn2 lipase labile phospholipid prodrugs in conjunction with contact-facilitated drug delivery offer an important advancement in Nanomedicine. Many drugs incorporated into nanosystems, targeted or not, are substantially lost during circulation to the target. However, favorably altering the pharmacokinetics and volume of distribution of systemic drug delivery can offer greater efficacy with lower toxicity, leading to new prolonged-release nanoexcipients. However, the concept of achieving Paul Erhlich's inspired vision of a ‘magic bullet’ to treat disease has been largely unrealized due to unstable nanomedicines, nanosystems achieving low drug delivery to target cells, poor intracellular bioavailability of endocytosed nanoparticle payloads, and the substantial biological barriers of extravascular particle penetration into pathological sites. As shown here, Sn2 phospholipid prodrugs in conjunction with contact-facilitated drug delivery prevent premature drug diffusional loss during circulation and increase target cell bioavailability. The Sn2 phospholipid prodrug approach applies equally well for vascular constrained lipid-encapsulated particles and micelles the size of proteins that penetrate through naturally fenestrated endothelium in the bone marrow or thin-walled venules of an inflamed microcirculation. At one time Nanomedicine was considered a ‘Grail Quest’ by its loyal opposition and even many in the field adsorbing the pains of a long-learning curve about human biology and particles. However, Nanomedicine with innovations like Sn2 phospholipid prodrugs has finally made ‘made the turn’ toward meaningful translational success

Pharmacogénétique du cytochrome P450 humain CYP3A5

Les CYP3A sont les P450 les plus abondants dans le foie où ils métabolisent plus de 50 % des médicaments. Le CYP3A5 n'est exprimé que dans 25 % de la population caucasienne. Une mutation (CYP3A5*3) entraînant un épissage alternatif a été associée à un faible niveau de CYP3A5. Un niveau d'ARNm CYP3A5 plus élevé chez les individus *1/*3 par rapport aux homozygotes *3/*3 nous a amené à rechercher les causes de cette variation. L'ARN *3 est plus instable et sa dégradation est réalisée par la NMD (nonsense mediated mRNA decay). Le génotype CYP3A5 a des conséquences en clinique. Nous avons mis au point une technique de génotypage informationnel basé sur la PCR quantitative permettant de déterminer en une seule réaction le génotype et le phénotype CYP3A5. Cette technique permettrait d'ajuster les doses de molécules de faible index thérapeutique lorsque leur pharmacocinétique dépend du CYP3A5. Cette technique peut être généralisée à l'étude des gènes épissés alternativement.CYP3A are the most abundant P450 in the human liver where they metabolize more than 50% of drugs. CYP3A5 is found in only 25% of the Caucasian population. A SNP (CYP3A5*3) yielding to alternative splicing was associated with low CYP3A5 protein content. A higher CYP3A5 mRNA level found in *1/*3 as compared to *3/*3 individuals led us to investigate the mechanism underlying this difference. CYP3A5*3 mRNA was unstable and its degradation was mediated by nonsense mediated mRNA decay (NMD). CYP3A5 genotype has consequences in clinics. We describe a new informative genotyping assay based on quantitative real-time PCR, allowing the determination of CYP3A5 genotype and phenotype in one single step. This assay could be used to improve the dosage of drugs metabolized by CYP3A5 having a narrow therapeutic window. This assay can be generalized to the study of alternatively spliced genesPARIS-BIUP (751062107) / SudocSudocFranceF

INDUCTION DES CYTOCHROMES P450 IIB AU COURS DE L'ONTOGENESE CHEZ LE RAT : INFLUENCE DES TYPES CELLULAIRES HEPATIQUES

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