Drug and Alcohol Rehabilitation: Gestational Age-Dependent Changes in Gene Expression of Metabolic Enzymes and Transporters in Pregnant Mice.

Gestational Age-Dependent Changes in Gene Expression of Metabolic Enzymes and Transporters in Pregnant Mice.

Filed under: Drug and Alcohol Rehabilitation

Drug Metab Dispos. 2012 Nov 21;
Shuster DL, Bammler TK, Beyer RP, Macdonald JW, Tsai JM, Farin FM, Hebert MF, Thummel KE, Mao Q

Pregnancy-induced changes in drug pharmacokinetics can be explained by changes in expression of drug-metabolizing enzymes and transporters and/or normal physiology. In this study, we determined gestational age-dependent expression profiles for all metabolic enzyme and transporter genes in the maternal liver, kidney, small intestine, and placenta of pregnant mice by microarray analysis. We specifically examined the expression of genes important for xenobiotic, bile acid, and steroid hormone metabolism and disposition, namely, cytochrome P450’s (Cyp), UDP-glucuronosyltranserases (Ugt), sulfotransferases (Sult), and ATP-binding cassette (Abc), solute carrier (Slc), and solute carrier organic anion (Slco) transporters. Few Ugt and Sult genes were affected by pregnancy. Cyp17a1 expression in the maternal liver increased 3-10-fold during pregnancy, which was the largest observed change in the maternal tissues. Cyp1a2, most Cyp2 isoforms, Cyp3a11, and Cyp3a13 expression in the liver decreased on gestation days (gd) 15 and 19 compared to non-pregnant controls (gd 0). In contrast, Cyp2d40, Cyp3a16, Cyp3a41a, Cyp3a41b, and Cyp3a44 in the liver were induced throughout pregnancy. In the placenta, Cyp expression on gd 10 and 15 was up-regulated compared to gd 19. Notable changes were also observed in Abc and Slc transporters. Abcc3 expression in the liver and Abcb1a, Abcc4, and Slco4c1 expression in the kidney were down-regulated on gd 15 and 19. In the placenta, Slc22a3 (Oct3) expression on gd 10 was 90% lower than that on gd 15 and 19. This study demonstrates important gestational age-dependent expression of metabolic enzyme and transporter genes, which may have mechanistic relevance to drug disposition in human pregnancy.
HubMed – drug

Increased Hospital Stay and Allograft Disfunction in Renal Transplanted Patients with CYP2C19 AA Variant in SNP RS4244285.

Filed under: Drug and Alcohol Rehabilitation

Drug Metab Dispos. 2012 Nov 21;
Boso V, Herrero MJ, Bea S, Galiana M, Marrero P, Marques MR, Hernandez J, Sanchez-Plumed J, Poveda JL, Alino SF

Pharmacogenetics correlates certain genetic variants, as Single Nucleotide Polymorphisms, SNPs, with blood drug levels, efficacy and adverse effects of the treatment. Tacrolimus is mainly metabolized via CYP3A4/5, whereas CYP2C19 and CYP3A4/5 are responsible of omeprazole metabolism. Omeprazole inhibits tacrolimus metabolism via CYP3A5 in patients carrying variant alleles of CYP2C19, increasing tacrolimus blood concentrations. 75 renal transplanted patients, treated with tacrolimus and concomitant omeprazole, were genotyped in a panel of 37 SNPs employing Sequenom® MassArray. The patients with CYP2C19*2/*2 genotype (n=4) showed a post-transplantation hospital stay of 27.5 days (median, 95% CI: 23-39) against 12 days (median, 95%CI: 10-15) in patients CYP2C19*1/*1 or *1/*2 (n=71), (p=0.016, Kruskal-Wallis test).The difference in hospital stay was directly correlated with an increase in tacrolimus levels Cmin/(dose/weight), during the first week post-trasplantation (in 59 patients with levels data) (p=0.021, Kruskal-wallis), excluding the patients with atypical metabolisms due to CYP3A5*1/*3 or *1/*1 genotype. Recipients with CYP2C19*2/*2 genotype also showed allograft delayed function (acute tubular necrosis in 3 of them). Genotyping of CYP3A5 and CYP2C19 in renal transplantation should be considered of interest, when treating with tacrolimus and omeprazole since CYP2C19*2/*2 variant indirectly elicits an increase of tacrolimus blood levels and, in our study population, the adverse effects described.
HubMed – drug

Multiple factors modulate biofilm formation by the anaerobic pathogen Clostridium difficile.

Filed under: Drug and Alcohol Rehabilitation

J Bacteriol. 2012 Nov 21;
Ethapa T, Leuzzi R, Ng YK, Baban ST, Adamo R, Kuehne SA, Scarselli M, Minton NP, Serruto D, Unnikrishnan M

Bacteria within biofilms are protected from multiple stresses, including immune responses and antimicrobial agents. The biofilm forming ability of bacterial pathogens has been associated with increased antibiotic resistance and chronic recurrent infections. While biofilms have been well studied for several gut pathogens, little is known about biofilm formation by anaerobic gut species. The obligate anaerobe Clostridium difficile causes C. difficile infection (CDI), a major health-care-associated problem primarily due to the high incidence of recurring infections. C. difficile colonizes the gut when the normal intestinal microflora is disrupted by antimicrobial agents; however the factors or processes involved in gut colonization during infection remain unclear. We demonstrate that clinical C. difficile strains, 630 and the hypervirulent strain R20291, form structured biofilms in vitro, with R20291 accumulating substantially more biofilm. Microscopic and biochemical analyses show multiple layers of bacteria encased in a biofilm matrix containing proteins, DNA and polysaccharide. Employing isogenic mutants, we show that virulence-associated proteins, Cwp84, flagella and a putative quorum sensing regulator, LuxS are all required for maximal biofilm formation by C. difficile. Interestingly, a mutant in Spo0A, a transcription factor that controls spore formation, was defective for biofilm formation, indicating a possible link between sporulation and biofilm formation. Furthermore, we demonstrate that bacteria in clostridial biofilms are more resistant to high concentrations of vancomycin, a drug commonly used for treatment of CDI. Our data suggest that biofilm formation by C. difficile is a complex multifactorial process and may be a crucial mechanism for clostridial persistence in the host.
HubMed – drug

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