CYP3A4, the most abundant cytochrome P450 enzyme in the human liver and small intestine, is responsible for the metabolism of about 50% of all marketed drugs. Numerous pathophysiological factors, such as diabetes and obesity, were shown to affect CYP3A activity. Evidences suggest that drug disposition is altered in type 1 (T1D) and type 2 diabetes (T2D). The objective was to evaluate the effect of T1D and T2D on hepatic and intestinal CYP3a drug-metabolizing activity/expression in mice. Hepatic and intestinal microsomes were prepared from streptozotocin-induced T1D, db/db T2D and control mice. Domperidone was selected as a probe substrate for CYP3a and formation of five of its metabolites was evaluated using high performance liquid chromatography. Hepatic CYP3a protein and mRNA expression were assessed by Western blot and reverse-transcription quantitative polymerase chain reaction respectively. Hepatic microsomal CYP3a activity was significantly increased in both T1D and T2D groups versus control group. Intestinal CYP3a activity was also significantly increased in both T1D and T2D groups. Moreover, significant increases of both hepatic CYP3a mRNAs and protein expression were observed in both T1D and T2D groups versus control group. Additional experiments with testosterone further validated the increased activity of CYP3a under the effect of both T1D and T2D. Although differences exist in the pathophysiological insults associated with T1D and T2D, our results suggest that these two distinct diseases may have the same modulating effect on the regulation of CYP3a, ultimately leading to variability in drug response, ranging from lack of effect to life-threatening toxicity.

Objective: The mechanisms of radiation-induced DNA damage can be understood via the fundamental acquisition of knowledge through a combination of experiments and modeling. Currently, most biological experiments are performed by irradiating an entire cell population, whereas modeling of radiation-induced effects is usually performed via Monte Carlo simulations with track structure codes coupled to realistic DNA geometries of a single-cell nucleus. However, the difference in scale between the two methods hinders a direct comparison because the dose distribution in the cell population is not necessarily uniform owing to the stochastic nature of the energy deposition. Thus, this study proposed the MINAS TIRITH tool to model the distribution of radiation-induced DNA damage in a cell population. Approach: The proposed method is based on precomputed databases of microdosimetric parameters and DNA damage distributions generated using the Geant4-DNA Monte Carlo Toolkit. First, a specific energy z was assigned to each cell of an irradiated population for a particular absorbed dose D_abs, following microdosimetric formalism. Then, each cell was assigned a realistic number of DNA damage events according to the specific energy z, respecting the stochastic character of its occurrence. Main results: This study validated the MINAS TIRITH tool by comparing its results with those obtained using the Geant4-DNA track structure code and a Geant4-DNA based simulation chain for DNA damage calculation. The different elements of comparison indicated consistency between MINAS TIRITH and the Monte Carlo simulation in case of the dose distribution in the population and the calculation of the amount of DNA damage. Significance: MINAS TIRITH is a new approach for the calculation of radiation-induced DNA damage at the cell population level that facilitates reasonable simulation times compared to those obtained with track structure codes. Moreover, this tool enables a more direct comparison between modeling and biological experimentation.

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The AMANDE facility produces monoenergetic neutron fields from 2 keV to 20 MeV for metrological purposes. To be considered as a reference facility, fluence and energy distributions of neutron fields have to be determined by primary measurement standards. For this purpose, a micro Time Projection Chamber is being developed to be dedicated to measure neutron fields with energy ranging from 8 keV up to 1 MeV. In this work we present simulations showing that such a detector, which allows the measurement of the ionization energy and the 3D reconstruction of the recoil nucleus, provides the determination of neutron energy and fluence of these neutron fields.

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The racemization rate constant for aspartic acid has been determined from the D/L isomeric ratio in four strata of radiocarbon dated woodrat midden in Arizona. Two different methods of stereospecifically deaminating L-aspartic acid prior to the assay are compared. It is found that pure L-amino acid oxidase pretreatment of the DL aspartic acid mixture requires one less step than treatment with crude, dialyzed venom (Crotalus viridis) but that the two methods give the same results. Application of the theory of amino acid racemization dating is discussed in the context of the steric properties ofthe protein environment in which the racemization actually occurs.

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