The cytochromes P450 (CYPs) are very efficient catalysts of foreign compound metabolism and are responsible for the major part of metabolism of clinically important drugs. The enzymes are important ...in cancer since they (a) activate dietary and environmental components to ultimate carcinogens, (b) activate or inactivate drugs used for cancer treatment, and (c) are potential targets for anticancer therapy. The genes encoding the CYP enzymes active in drug metabolism are highly polymorphic, whereas those encoding metabolism of precarcinogens are relatively conserved. A vast amount of literature is present where investigators have tried to link genetic polymorphism in CYPs to cancer susceptibility, although not much conclusive data have hitherto been obtained, with exception of CYP2A6 polymorphism and tobacco induced cancer, to a great extent because of lack of important functional polymorphisms in the genes studied. With respect to anticancer treatment, the genetic CYP polymorphism is of greater importance, where treatment with tamoxifen, but also with cyclophosphamide and maybe thalidomide is influenced by CYP genetic variants. In the present review we present updates on CYP genetics, cancer risk and treatment and also epigenetic aspects of interindividual variability in CYP expression and the use of these enzymes as targets for cancer therapy. We conclude that the CYP polymorphism does not predict cancer susceptibility to any large extent but that this polymorphism might be an important factor for optimal cancer therapy using selected anticancer agents.
Important interindividual differences in drug pharmacokinetics cause absence of drug response or adverse drug reactions in significant fractions of the populations. The identification of the major ...enzymes participating, and the elucidation of the genetic basis for this variation in particular among cytochromes P450, provide tools for a personalized medicine treatment, which can make drug therapy much more effective at a lower cost. Much of the pioneering work linking drug metabolizing phenotype to genetic polymorphism among the P450 enzymes has been carried out at Karolinska Institutet. In this review we give a background and description of this work as well as the important implications for future medicine.
•Method translates water consumption to area-equivalent of mean monthly flow.•This is compared to an assigned share of “safe operating space” at watershed-level.•Method is demonstrated on case study ...for two illustrative sharing principles.•Work contributes to improving planetary boundaries-based life cycle assessments.
Existing methods for applying the planetary boundary concept in life cycle assessment are not sufficiently spatially and temporally resolved. Here, we develop a new method for freshwater use based on the safe operating space (SOS) at watershed-level. The SOS is based on the concept of environmental flow requirements, which is the share of mean monthly flow that should be reserved to achieve or maintain “fair conditions” of aquatic ecosystems. The method is composed of two steps. First, water consumption is multiplied by a characterization factor, which converts it to an environmental impact, expressed as an area-equivalent of a watershed’s mean monthly flow. Second, the environmental impact is compared to an assigned share of SOS to determine if the activity causing it can be considered environmentally sustainable, with respect to a chosen principle for sharing the SOS.
The method is demonstrated for a case study on water consumed for irrigation in open-field tomato production in 27 watersheds, spanning 10 countries and 5 continents, based on data for 316 farms in the year 2014. Water consumption was modelled from crop characteristics, climatic data and the assumed type of irrigation system. Two principles, “status quo” and “gross value added”, were illustratively applied for the assignment of SOS to 1 tonne of tomatoes.
The characterization factors developed span two orders of magnitude from 10th to 90th percentile, which shows the relevance of a spatially and temporally explicit assessment. In the case study, the characterization factors largely determine the high variability in the resulting environmental impacts between watersheds, which ranged from 400 m2 to 50,000 m2 per tonne of tomatoes. The analysis would suggest that the freshwater use by current tomato farming is environmentally sustainable in all months in a maximum of 2 of the 27 watersheds with respect to the two principles applied for sharing the SOS.
The method can be used as a basis to identify potential “planetary boundary hotspots” in the life cycle of products and to inform appropriate interventions. Two key challenges are the lack of appropriate spatial and temporal data in current life cycle inventories and the choice of sharing principle for assigning the SOS.
Corporations and other multinational institutions are increasingly looking to evaluate their innovation and procurement decisions over a range of environmental criteria, including impacts on ...ecosystem services according to the spatial configuration of activities on the landscape. We have developed a spatially explicit approach and modeled a hypothetical corporate supply chain decision representing contrasting patterns of land-use change in four regions of the globe. This illustrates the effect of introducing spatial considerations in the analysis of ecosystem services, specifically sediment retention. We explored a wide variety of contexts (Iowa, USA; Mato Grosso, Brazil; and Jiangxi and Heilongjiang in China) and these show that per-area representation of impacts based on the physical characterization of a region can be misleading. We found two- to five-fold differences in sediment export for the same amount of habitat conversion within regions characterized by similar physical traits. These differences were mainly determined by the distance between land use changes and streams. The influence of landscape configuration is so dramatic that it can override wide variation in erosion potential driven by physical factors like soil type, slope, and climate. To minimize damage to spatially-dependent ecosystem services like water purification, sustainable sourcing strategies should not assume a direct correlation between impact and area but rather allow for possible nonlinearity in impacts, especially in regions with little remaining habitat and highly variable hydrological connectivity.
Interindividual variability in xenobiotic metabolism and drug response is extensive and genetic factors play an important role in this variation. A majority of clinically used drugs are substrates ...for the cytochrome P450 (CYP) enzyme system and interindividual variability in expression and function of these enzymes is a major factor for explaining individual susceptibility for adverse drug reactions and drug response. Because of the existence of many polymorphic CYP genes, for many of which the number of allelic variants is continually increasing, a universal and official nomenclature system is important. Since 1999, all functionally relevant polymorphic CYP alleles are named and published on the Human Cytochrome P450 Allele (CYP-allele) Nomenclature Web site (http://www.cypalleles.ki.se). Currently, the database covers nomenclature of more than 660 alleles in a total of 30 genes that includes 29 CYPs as well as the cytochrome P450 oxidoreductase (POR) gene. On the CYP-allele Web site, each gene has its own Webpage, which lists the alleles with their nucleotide changes, their functional consequences, and links to publications identifying or characterizing the alleles. CYP2D6, CYP2C9, CYP2C19, and CYP3A4 are the most important CYPs in terms of drug metabolism, which is also reflected in their corresponding highest number of Webpage hits at the CYP-allele Web site.The main advantage of the CYP-allele database is that it offers a rapid online publication of CYP-alleles and their effects and provides an overview of peer-reviewed data to the scientific community. Here, we provide an update of the CYP-allele database and the associated nomenclature.
Many companies are making ambitious pledges to achieve positive impacts for climate and nature by financing restoration of carbon- and biodiversity- rich natural habitats. However, companies cannot ...make evidence-based choices that will deliver successful restoration if the scientific information required to guide investment has not been synthesised in a way that they can use, or there are knowledge gaps. To explore this issue, share information, and identify knowledge gaps and research priorities, we bring together researchers, a conservation NGO and a multinational consumer goods company (Unilever), focusing on Southeast Asian rainforests. These habitats offer significant restoration opportunities for carbon and biodiversity in areas that have been degraded by commercial logging and agriculture. We find that procedures for carbon restoration are much better developed than those for biodiversity, and that new research is urgently needed to deliver evidence-based biodiversity restoration. Companies need to be confident that their actions are fit-for-purpose to meet their environmental pledges. Achieving successful restoration outcomes will require co-designed projects with the potential to deliver positive co-benefits for carbon, biodiversity and local livelihoods.
•Many companies are making climate net-zero and biodiversity pledges to restore rainforest.•Choices of projects to finance need to be underpinned by scientific evidence.•We synthesise information on restoring carbon and nature in Southeast Asian forests.•Procedures for carbon restoration are better developed than those for biodiversity.•We outline research priorities to ensure company choices are fit-for-purpose.
Vitellointestinal duct (VID) anomalies have been described extensively in the literature. However, an everted VID with prolapse of ileum arising from an omphalocele is rare, and its appearance at ...birth can be alarming and can present a diagnostic challenge. We describe a baby born to a teenage diabetic mother who was noted to have a strange exophytic mass arising from the abdominal wall. Antenatal scans had revealed multiple other malformations but not an omphalocele. He was operated on early, and the diagnosis of a patent VID with prolapse of the ileum arising from an omphalocele was only confirmed intraoperatively. The duct was resected, the ileum closed primarily and primary closure of the abdominal wall was performed without tension. He recovered well postoperatively. A brief review of similar cases is included.
Databases in the area of pharmacogenetics Sim, Sarah C.; Altman, Russ B.; Ingelman-Sundberg, Magnus
Human mutation,
20/May , Letnik:
32, Številka:
5
Journal Article
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