Renal drug metabolism in humans: the potential for drug–endobiotic interactions involving cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT)

This item is under embargo for a period of 12 months from the date of publication, in accordance with the publisher's policy. ‘This is the peer reviewed version of the following article: Knights, K. M., Rowland, A. and Miners, J. O. (2013), Renal drug metabolism in humans: the potential for drug– endobiotic interactions involving cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT). British Journal of Clinical Pharmacology, 76: 587–602, which has been published in final form at doi:10.1111/bcp.12086. This article may be used for non-commercial purposes in accordance With Wiley Terms and Conditions for selfarchiving'.Although knowledge of human renal cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) enzymes and their role in xenobiotic and endobiotic metabolism is limited compared with hepatic drug and chemical metabolism, accumulating evidence indicates that human kidney has significant metabolic capacity. Of the drug metabolizing P450s in families 1 to 3, there is definitive evidence for only CYP 2B6 and 3A5 expression in human kidney. CYP 1A1, 1A2, 1B1, 2A6, 2C19, 2D6 and 2E1 are not expressed in human kidney, while data for CYP 2C8, 2C9 and 3A4 expression are equivocal. It is further known that several P450 enzymes involved in the metabolism of arachidonic acid and eicosanoids are expressed in human kidney, CYP 4A11, 4F2, 4F8, 4F11 and 4F12. With the current limited evidence of drug substrates for human renal P450s drug–endobiotic interactions arising from inhibition of renal P450s, particularly effects on arachidonic acid metabolism, appear unlikely. With respect to the UGTs, 1A5, 1A6, 1A7, 1A9, 2B4, 2B7 and 2B17 are expressed in human kidney, whereas UGT 1A1, 1A3, 1A4, 1A8, 1A10, 2B10, 2B11 and 2B15 are not. The most abundantly expressed renal UGTs are 1A9 and 2B7, which play a significant role in the glucuronidation of drugs, arachidonic acid, prostaglandins, leukotrienes and P450 derived arachidonic acid metabolites. Modulation by drug substrates (e.g. NSAIDs) of the intrarenal activity of UGT1A9 and UGT2B7 has the potential to perturb the metabolism of renal mediators including aldosterone, prostaglandins and 20-hydroxyeicosatetraenoic acid, thus disrupting renal homeostasis

Computer graphic control over human face and head appearance: to, genetic optimisation of perceptual characteristics

The aims of this thesis are two-fold. The first is to develop computer graphics that allow quantitative manipulation of complex visual stimuli. The second is to show that such techniques have utility in the domain of perceptual psychology. There are three main sections to this thesis. The first section creates methods for performing transformations of facial appearance along particular perceptual dimensions. This work begins with 2-D image manipulations and then extends the general principles to 3-D. Effectiveness of the techniques is illustrated with plates showing transformation in age, gender and identity. The second section uses Genetic Algorithms to control the appearance of 3-D computer graphics objects and investigates methods of evolving objects that embody various consumer concepts. Computer graphic models of shampoo bottles are successfully evolved to satisfy a selection of aesthetic and perceptual characteristics. The final section returns to facial stimuli and extends the Genetic Algorithm approach to investigate aesthetic preference for 3-D facial surfaces. The study shows that individual human subjects can evolve facial surfaces based upon their own attractiveness preferences. The faces evolved are non-average and there is consistency between subjects about preferred characteristics. The three parts of this thesis have different theoretical backgrounds and literature relevant to each topic is therefore reviewed at the start of each section

What is Professionalism? The Validation of a Comprehensive Model of Professionalism

Professionalism is a term frequently used in organizations yet perceptions of what it means differ from person to person. Given its frequent use and its link to various job outcomes, such as organizational commitment (Bartol, 1979), there is a need to have a universal definition of professionalism. While there are existing models of professionalism these models are typically developed for a specific field or industry. Thus, there is also a need for a comprehensive model of professionalism that can be used across multiple fields and industries. This study worked to develop a model of professionalism that creates a comprehensive model that addresses both of these issues using eleven existing measures of professionalism as its foundation. Four dimensions of professionalism were identified via these models and defined using a combination of existing research and researcher expertise. These dimensions were divided into elements which were used as items in a measure to validate the new model. A five-factor model demonstrated the best fit and was found to have both convergent and discriminant validity

Estimates for local and movement-based transmission of bovine tuberculosis in British cattle

Both badgers and livestock movements have been implicated in contributing to the ongoing epidemic of bovine tuberculosis (BTB) in British cattle. However, the relative contributions of these and other causes are not well quantified. We used cattle movement data to construct an individual (premises)-based model of BTB spread within Great Britain, accounting for spread due to recorded cattle movements and other causes. Outbreak data for 2004 were best explained by a model attributing 16% of herd infections directly to cattle movements, and a further 9% unexplained, potentially including spread from unrecorded movements. The best-fit model assumed low levels of cattle-to-cattle transmission. The remaining 75% of infection was attributed to local effects within specific high-risk areas. Annual and biennial testing is mandatory for herds deemed at high risk of infection, as is pre-movement testing from such herds. The herds identified as high risk in 2004 by our model are in broad agreement with those officially designated as such at that time. However, border areas at the edges of high-risk regions are different, suggesting possible areas that should be targeted to prevent further geographical spread of disease. With these areas expanding rapidly over the last decade, their close surveillance is important to both identify infected herds quickly, and limit their further growth

A Comparison of the Genetic Factors Influencing Host Response to Infection with One of Two Isolates of Porcine Reproductive and Respiratory Syndrome Virus

Host genetic differences in viral load (VL) and weight gain (WG) during porcine reproductive and respiratory syndrome virus (PRRSV) challenge were assessed for thirteen trials of ~200 commercial crossbred piglets each, from several different commercial suppliers. Piglets were experimentally infected with PRRSV isolates NVSL-97-7895 (NVSL) or KS-2006-72109 (KS06). VL and WG were moderately heritable and were antagonistically related for both virus isolates. The genetic correlation of host response to NVSL with host response to KS06 was high for both VL and WG. Consistent with previous findings, animals that were heterozygous (AB) for the WUR10000125 (WUR) marker on Chromosome 4 (SSC4) had significantly lower VL than their AA counterparts when infected with either virus isolate; however, a significant increase in WG was only observed when piglets were infected with the NVSL isolate. These results suggest that selecting for increased resistance or reduced susceptibility to PRRSV may be effective across virus isolates. Selecting for the AB genotype for WUR is expected to reduce VL across PRRSV isolates but its effect on WG during infection may differ between virus isolates

Factors Associated with N-specific IgG Response in Piglets Experimentally Infected with Porcine Reproductive and Respiratory Syndrome Virus

This study examined serum porcine reproductive and respiratory syndrome virus (PRRSV) N protein-specific IgG levels from sera collected from 464 Large White-Landrace commercial crossbred piglets from three separate experimental infection trials with PRRSV isolate NVSL-97- 7895. IgG levels at 42 days post infection (dpi) were measured by fluorescent microsphere immunoassay, herein referred to as total antibody (tAb) response. tAb levels were assessed for an association with different disease-related traits, the presence of a heritable genetic component, and for genomic regions associated with tAb response. tAb response was negatively associated with viral load (VL) and weight gain from 28-42 dpi (WG) and positively associated with virus rebound (REB) and neutralizing antibody (nAb) levels. Furthermore, tAb response had a heritable genetic component, with a major QTL located on chromosome 7 in the major histocompatibility complex (MHC), whereby heterozygous individuals had a lower tAb response and increased weight gain from 28-42 dpi. These results suggest that genetic selection for tAb response may be useful for selecting for pigs that have increased resistance or reduced susceptibility to PRRSV

Validation of the Effects of a SNP on SSC4 Associated with Viral Load and Weight Gain in Piglets Experimentally Infected with a 2006 PRRS Virus Isolate

Host genetic differences in viral load (VL) and weight gain (WG) during challenge were assessed for five trials of ~200 commercial crossbred piglets each, all from different commercial suppliers. Piglets were experimentally infected with porcine reproductive and respiratory syndrome virus (PRRSV) isolate KS-2006-72109 in order to validate the effects of a SNP previously identified on SSC4 (WUR10000125), whereby AB individuals had increased WG and reduced VL when experimentally infected with PRRSV isolate NVSL-97-7895. VL was defined as the area under the curve of logged viremia from 0-21 dpi. WG was defined as the weight gained from 0-42 dpi. The SNP effects on VL and WG were assessed. AB individuals had higher WG and lower VL than AA individuals, suggesting this marker may be useful for genetic selection of pigs for increased resistance or reduced susceptibility to PRRSV isolates that differ genetically and possibly pathogenically