The erythromycin breath test as a predictor of cyclosporine blood levels

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109915/1/cptclpt1990126.pd

Differential regulation of liver P-450III cytochromes in choline-deficient rats: Implications for the erythromycin breath test as a parameter of liver function

Progressive liver fibrosis in rats develops when they are fed a diet deficient in choline. This diet also results in a pronounced and selective decrease in the liver microsomal content of a phase I drug—metabolizing enzyme belonging to the cytochrome P-450III gene family. Because P-450III cytochromes characteristically catalyze the N -demethylation of erythromycin, we believed that the production of breath CO 2 from erythromycin would be dramatically reduced in choline-deficient rats. However, when 12 choline-deficient rats were compared with 9 control rats, the reduction in CO 2 production from erythromycin (mean decrease 71%) was essentially identical to that from aminopyrine (mean decrease 69%), a substrate believed to be metabolized normally by the hepatocyte in fibrotic liver disease. Furthermore, we found that the relative erythromycin and aminopyrine demethylase activities were comparable when measured in vitro in liver microsomes prepared from the choline-deficient rats. To determine the molecular basis for the erythromycin demethylase activity in the choline-deficient rats, the liver microsomes were subjected to immunoblot analysis using a variety of polyclonal and monoclonal antibodies capable of distinguishing individual P-450III—related proteins. Our studies confirm that a major erythromycin demethylase belonging to the P-450III family, termed P-450p, was greatly reduced in the choline-deficient rat liver. However, the specific concentration of a second P-450p—related protein was essentially normal and that of a third P-450p—related protein was actually increased in the choline-deficient rat liver. These changes occurred over weeks and months on the choline-deficient diet and are not consistent with “feminization” of the liver. The P-450p—related proteins appeared to catalyze erythromycin demethylase activity because antibodies recognizing them inhibited the majority (62%) of this activity in choline-deficient rat microsomes. Finally, RNA extracted from choline-deficient rat livers was hybridized on Northern blots with synthetic oligonucleotide probes that identify the only two known rat P-450III cDNAs, PCN-1 and PCN-2. Prolonged choline deficiency appeared to have no consistent effects on expression of these RNA species. We conclude that despite the down-regulation of a major erythromycin demethylase, this catalytic activity is relatively preserved in the choline-deficient rat, at least in part because of differential regulation of P-450III cytochromes. Erythromycin therefore appears to offer little advantage over aminopyrine as a substrate for assessing liver function in this model of chronic liver disease. (HEPATOLOGY 1990;12:1371–1378).Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/38340/1/1840120619_ftp.pd

Comparison of urinary 6‐β‐cortisol and the erythromycin breath test as measures of hepatic P450IIIA (CYP3A) activity

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/110077/1/cptclpt1992140.pd

Cyclosporin toxicity at therapeutic blood levels and cytochrome P-450 IIIA

A 40-year-old male liver allograft recipient had neurological dysfunction and renal failure while his cyclosporin blood levels were in the therapeutic range; these features recurred on rechallenge. The hypothesis that this toxic effect might have resulted from abnormal metabolism of cyclosporin by liver cytochrome P-450 IIIA was investigated with the [14C]erythromycin breath test, which is a measure of this enzyme's activity. P-450 IIIA activity was decreased compared with that in controls, including other liver transplant recipients. Pretreatment with rifampicin, an inducer of P-450 IIIA, increased enzyme activity. After treatment with rifampicin the patient could be rechallenged with cyclosporin at a dose almost twice that which had previously been toxic. The patient died during a second transplantation and the microsomal content of P-450 IIIA was found to be low in the first transplant.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28757/1/0000587.pd

Determining the Cosmic Distance Scale from Interferometric Measurements of the Sunyaev-Zel'dovich Effect

We determine the distances to 18 galaxy clusters with redshifts ranging from z~0.14 to z~0.78 from a maximum likelihood joint analysis of 30 GHz interferometric Sunyaev-Zel'dovich effect (SZE) and X-ray observations. We model the intracluster medium (ICM) using a spherical isothermal beta model. We quantify the statistical and systematic uncertainties inherent to these direct distance measurements, and we determine constraints on the Hubble parameter for three different cosmologies. These distances imply a Hubble constant of 60 (+4, -4) (+13, -18) km s-1 Mpc-1 for an Omega_M = 0.3, Omega_Lambda = 0.7 cosmology, where the uncertainties correspond to statistical followed by systematic at 68% confidence. With a sample of 18 clusters, systematic uncertainties clearly dominate. The systematics are observationally approachable and will be addressed in the coming years through the current generation of X-ray satellites (Chandra & XMM-Newton) and radio observatories (OVRO, BIMA, & VLA). Analysis of high redshift clusters detected in future SZE and X-ray surveys will allow a determination of the geometry of the universe from SZE determined distances.Comment: ApJ Submitted; 40 pages, 9 figures (fig 3 B&W for size constraint), 13 tables, uses emulateapj5 styl

Lipidomics Reveals Early Metabolic Changes in Subjects with Schizophrenia: Effects of Atypical Antipsychotics

There is a critical need for mapping early metabolic changes in schizophrenia to capture failures in regulation of biochemical pathways and networks. This information could provide valuable insights about disease mechanisms, trajectory of disease progression, and diagnostic biomarkers. We used a lipidomics platform to measure individual lipid species in 20 drug-naïve patients with a first episode of schizophrenia (FE group), 20 patients with chronic schizophrenia that had not adhered to prescribed medications (RE group), and 29 race-matched control subjects without schizophrenia. Lipid metabolic profiles were evaluated and compared between study groups and within groups before and after treatment with atypical antipsychotics, risperidone and aripiprazole. Finally, we mapped lipid profiles to n3 and n6 fatty acid synthesis pathways to elucidate which enzymes might be affected by disease and treatment. Compared to controls, the FE group showed significant down-regulation of several n3 polyunsaturated fatty acids (PUFAs), including 20:5n3, 22:5n3, and 22:6n3 within the phosphatidylcholine and phosphatidylethanolamine lipid classes. Differences between FE and controls were only observed in the n3 class PUFAs; no differences where noted in n6 class PUFAs. The RE group was not significantly different from controls, although some compositional differences within PUFAs were noted. Drug treatment was able to correct the aberrant PUFA levels noted in FE patients, but changes in re patients were not corrective. Treatment caused increases in both n3 and n6 class lipids. These results supported the hypothesis that phospholipid n3 fatty acid deficits are present early in the course of schizophrenia and tend not to persist throughout its course. These changes in lipid metabolism could indicate a metabolic vulnerability in patients with schizophrenia that occurs early in development of the disease. © 2013 McEvoy et al

Athletic Trainers and Sport Psychology: Knowledge, Experience and Attitudes

titles. Certified athletic trainers (ATCs) play a unique role in sport environments as the primary medical staff available to athletes. Thus, ATCs are well positioned to oversee athletes' physical and psychological well-being. Although sport psychologists (SPs) have been identified as a potential resource for ATCs, previous studies have reported a lack of collaboration between SPs and ATCs. This study aimed to (a) examine ATCs' views regarding professional roles for both ATCs and SPs, (b) explore ATCs' referral behaviors, (c) evaluate ATCs belief in the credibility of sport psychology across demographic (i.e., gender, age) and experiential variables (i.e., access to SPs), and (d) examine ATCs' involvement in sport psychology. Four hundred ninety-six ATCs (265 men, 231 women) completed and returned the questionnaire. ATCs viewed assisting in the psychological recovery of athletes as the most acceptable professional role for fellow ATCs; aiding in the psychological recovery of injured athletes and teach mental skills were identified by ATCs as the most appropriate roles for SPs. In considering an athlete experiencing interpersonal difficulties (e.g., relationship problems), a mixed design ANOVA revealed a ATC sex by referral option interaction; female and male ATCs indicated they would likely refer the athlete to a counselor/therapist, followed by a SP, however, female ATCs reported a greater likelihood of referring to a counselor/therapist than male ATCs whereas male ATCs indicated a greater likelihood of referring to a SP. Further, ATCs' regular access to SPs and completion of formal sport psychology coursework were identified as variables associated with greater belief in the credibility of sport psychology. These results suggest that access and previous experience with SPs remain significant variables associated with ATCs views about, and belief in, the work of SPs. Implications for sport psychology professionals and recommendations for future research are discussed

Interpatient heterogeneity in expression of CYP3A4 and CYP3A5 in small bowel: Lack of prediction by the erythromycin breath test

The CYP3A subfamily of cytochromes P450 metabolize many medications and environmental contaminants. CYP3A4 and, in 25% of patients, CYP3A5 seem to be the major CYP3A genes expressed in adult liver. Hepatic levels of CYP3A4 can be estimated by the erythromycin breath test and vary at least 10-fold among patients. CYP3A4 has also been shown to be present in small bowel where it is responsible for significant "first-pass" metabolism of orally administered substrates. However, it is not known whether there is significant interindividual variability in the intestinal expression of CYP3A4, or whether the liver and intestinal catalytic activities of CYP3A4 correlate within an individual. It is also not known whether CYP3A5 is expressed in the small intestine. To address these questions, we administered the erythromycin breath test to 20 patients and obtained biopsies from their small bowel. There was a 6-fold variation in CYP3A catalytic activity (midazolam hydroxylation), an 11-fold variation in CYP3A4 protein content, and an 8-fold variation in CYP3A4 mRNA content in intestinal biopsies. There was an excellent correlation between intestinal CYP3A4 protein level and catalytic activity (r = 0.86; p = 0.0001); however, neither parameter significantly correlated with hepatic CYP3A4 activity as measured by the erythromycin breath test result (r = 0.27; p = 0.24 and r = 0.33; p = 0.15, respectively). We also found that CYP3A5 protein was readily detectable in biopsies from 14 (70%) of the patients, indicating that CYP3A5 is commonly expressed in human small intestine

Cyp3A gene expression in human gut epithelium

CYP3A4, a major Phase I xenobiotic metabolizing enzyme present in liver, is also present in human small bowel epithelium where it appears to catalyse significant 'first pass' metabolism of some drugs. To determine whether CYP3A4 or the related enzymes CYP3A3, CYP3A5, and CYP3A7 are present in other regions of the digestive tract, we used CYP3A-specific antibodies to examine histological sections and epithelial microsomes obtained from a human organ donor. CYP3A-related proteins were detected in epithelia throughout the digestive tract and in gastric parietal cells, in pericentral hepatocytes, and in ductular cells of the pancreas. Immunoblot analysis suggested that the major CYP3A protein present in liver, jejunum, colon, and pancreas was CYP3A4 or CYP3A3, whereas CYP3A5 was the major protein present in stomach. Both CYP3A4 and CYP3A5 mRNA were detectable in all regions of the digestive tract using the polymerase chain reaction (PCR); however, only CYP3A4 could be detected by Northern blot analysis. CYP3A7 mRNA was consistently detected only in the liver by PCR and CYP3A3 mRNA was not detected in any of the tissues. We conclude that CYP3A4 and CYP3A5 are present throughout the human digestive tract and that differences in the expression of these enzymes may account for inter-organ differences in the metabolism of CYP3 A substrates