Aspects of marine geoscience: a review and thoughts on potential for observing active processes and progress through collaboration between the ocean sciences.

Much progress has been made in the UK in characterizing the internal structures of major physiographic features in the oceans and in developing understanding of the geological processes that have created or shaped them. UK researchers have authored articles of high impact in all areas described here. In contrast to terrestrial geoscience, however, there have been few instrumented observations made of active processes by UK scientists. This is an area that could be developed over the next decades in the UK. Research on active processes has the potential ability to engage the wider public: Some active processes present significant geo-hazards to populations and offshore infrastructure that require monitoring and there could be commercial applications of technological developments needed for science. Some of the suggestions could involve studies in shallow coastal waters where ship costs are much reduced, addressing tighter funding constraints over the near term. The possibilities of measuring aspects of volcanic eruptions, flowing lava, turbidity currents and mass movements (landslides) are discussed. A further area of potential development is in greater collaboration between the ocean sciences. For example, it is well known in terrestrial geomorphology that biological agents are important in modulating erosion and the transport of sediments, ultimately affecting the shape of the Earth's surface in various ways. The analogous effect of biology on large-scale geomorphology in the oceans is also known but remains poorly quantified. Physical oceanographic models are becoming increasingly accurate and could be used to study further the patterns of erosion, particle transport and deposition in the oceans. Marine geological and geophysical data could in turn be useful for further verification of such models. Adapting them to conditions of past oceans could address the shorter-period movements, such as due to internal waves and tides, which have been barely addressed in palaeoceanography.

Assessing cytochrome P450 and UDP-glucuronosyltransferase contributions to warfarin metabolism in humans.

As a step toward exploring a targeted metabolomics approach to personalized warfarin (Coumadin) therapy, we developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method capable of quantifying specific enantiomeric (R and S) contributions of warfarin (WAR) and the corresponding hydroxywarfarins (OH-WAR) and glucuronides (-GLUC) generated by cytochrome P450s (CYP) and UDP-glucuronosyltransferases (UGTs), respectively. Evaluation of quality control samples and three commercially available human samples showed that our analytical approach has the ability to measure 24 unique WAR metabolites in human urine. Evaluation of the human data also provides new insights for evaluating WAR toxicity and begins characterizing important UGT metabolic pathways responsible for WAR detoxification. Data revealed the significance of specific metabolites among patients and the corresponding enzymatic capacity to generate these compounds, including the first report of direct WAR glucuronidation. On the basis of total OH-WAR levels, (S)-7-OH-WAR was the predominant metabolite indicating the significance of CYP2C9 in WAR metabolism, although other CYP2C enzymes also contributed to clearance of this isomer. (R)-WAR hydroxylation to OH-WARs was more diverse among the patients as reflected in varying contributions of CYP1A2 and multiple CYP2C enzymes. There was wide variation in the glucuronidation of WAR and the OH-WARs with respect to the compounds and patients. 6- and 7-OH-WAR were primarily (>70%) excreted as glucuronides unlike 4'-OH-WAR and 8-OH-WAR. For all patients, UGT1A1 is likely responsible for 6-O-GLUC production, although UGT1A10 may also contribute in one patient. 7-O-GLUC levels reflected contributions from potentially five different UGT1A enzymes. In all cases, WAR, 4'-OH-WAR, 8-OH-WAR, and the corresponding glucuronides were minor metabolites with respect to the others. Taken together, these data suggest that both P450 and UGT reactions contribute to the generation of excretable products in human urine, thereby generating complex metabolic networks.

Glucuronidation of monohydroxylated warfarin metabolites by human liver microsomes and human recombinant UDP-glucuronosyltransferases.

Our understanding of human phase II metabolic pathways which facilitate detoxification and excretion of warfarin (Coumadin) is limited. The goal of this study was to test the hypothesis that there are specific human hepatic and extrahepatic UDP-glucuronosyltransferase (UGT) isozymes, which are responsible for conjugating warfarin and hydroxylated metabolites of warfarin. Glucuronidation activity of human liver microsomes (HLMs) and eight human recombinant UGTs toward (R)- and (S)-warfarin, racemic warfarin, and major cytochrome P450 metabolites of warfarin (4'-, 6-, 7-, 8-, and 10-hydroxywarfarin) has been assessed. HLMs, UGT1A1, 1A8, 1A9, and 1A10 showed glucuronidation activity toward 4'-, 6-, 7-, and/or 8-hydroxywarfarin with K(m) values ranging from 59 to 480 microM and V(max) values ranging from 0.03 to 0.78 microM/min/mg protein. Tandem mass spectrometry studies and structure comparisons suggested glucuronidation was occurring at the C4'-, C6-, C7-, and C8-positions. Of the hepatic UGT isozymes tested, UGT1A9 exclusively metabolized 8-hydroxywarfarin, whereas UGT1A1 metabolized 6-, 7-, and 8-hydroxywarfarin. Studies with extrahepatic UGT isoforms showed that UGT1A8 metabolized 7- and 8-hydroxywarfarin and that UGT1A10 glucuronidated 4'-, 6-, 7-, and 8-hydroxywarfarin. UGT1A4, 1A6, 1A7, and 2B7 did not have activity with any substrate, and none of the UGT isozymes evaluated catalyzed reactions with (R)- and (S)-warfarin, racemic warfarin, or 10-hydroxywarfarin. This is the first study identifying and characterizing specific human UGT isozymes, which glucuronidate major cytochrome P450 metabolites of warfarin with similar metabolic rates known to be associated with warfarin metabolism. Continued characterization of these pathways may enhance our ability to reduce life-threatening and costly complications associated with warfarin therapy.