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Survey of Drug Oxidation Activities in Hepatic and Intestinal Microsomes of Individual Common Marmosets, a New Nonhuman Primate Animal Model.

ABSTRACT: BACKGROUND:Common marmosets (Callithrix jacchus) are potentially useful nonhuman primate models for preclinical studies. Information for major drug-metabolizing cytochrome P450 (P450) enzymes is now available that supports the use of this primate species as an animal model for drug development. Here, we collect and provide an overview of information on the activities of common marmoset hepatic and intestinal microsomes with respect to 28 typical human P450 probe oxidations. RESULTS:Marmoset P450 2D6/8-dependent R-metoprolol O-demethylation activities in hepatic microsomes were significantly correlated with those of midazolam 1'- and 4-hydroxylations, testosterone 6?-hydroxylation, and progesterone 6?-hydroxylation, which are probe reactions for marmoset P450 3A4/5/90. In marmosets, the oxidation activities of hepatic microsomes and intestinal microsomes were roughly comparable for midazolam and terfenadine. Overall, multiple forms of marmoset P450 enzymes in livers and intestines had generally similar substrate recognition functionalities to those of human and/or cynomolgus monkey P450 enzymes. CONCLUSION:The marmoset could be a model animal for humans with respect to the first-pass extraction of terfenadine and related substrates. These findings provide a foundation for understanding individual pharmacokinetic and toxicological results in nonhuman primates as preclinical models and will help to further support understanding of the molecular mechanisms of human P450 function.

SUBMITTER: Uehara S

PROVIDER: S-EPMC6635653 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Survey of Drug Oxidation Activities in Hepatic and Intestinal Microsomes of Individual Common Marmosets, a New Nonhuman Primate Animal Model.

Uehara Shotaro S Oshio Toru T Nakanishi Kazuyuki K Tomioka Etsuko E Suzuki Miyu M Inoue Takashi T Uno Yasuhiro Y Sasaki Erika E Yamazaki Hiroshi H

Current drug metabolism 20190101 2

<h4>Background</h4>Common marmosets (Callithrix jacchus) are potentially useful nonhuman primate models for preclinical studies. Information for major drug-metabolizing cytochrome P450 (P450) enzymes is now available that supports the use of this primate species as an animal model for drug development. Here, we collect and provide an overview of information on the activities of common marmoset hepatic and intestinal microsomes with respect to 28 typical human P450 probe oxidations.<h4>Results</h ...[more]

PMID: 30280664

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Project description:IntroductionThe gray mouse lemur (Microcebus murinus) is an important nonhuman primate model in biomedical research. Numerous studies investigated mouse lemur behavior and possible factors underlying interindividual variation in both, animal personality and cognitive performance. Some effects, such as an age-related decline in executive functioning, have robustly been found across laboratory colonies; however, little is known about the brain structural substrates in mouse lemurs.MethodsHere, we provide first exploratory data linking in vivo magnetic resonance imaging of 34 mouse lemurs to performance in a standardized, touchscreen-based task on object discrimination and reversal learning as well as to animal personality under different scenarios in an open field.ResultsHigh interindividual variability in both brain morphometric and behavioral measurements was found, but only few significant correlations between brain structure and behavior were revealed: Object discrimination learning was linked to the volume of the hippocampus and to temporal lobe thickness, while reversal learning was linked to thalamic volume and the thickness of the anterior cingulate lobe. Emergence latency into the open field correlated with volume of the amygdala. General exploration-avoidance in the empty open-field arena correlated with thicknesses of the anterior cingulate lobe and fronto-parietal substructures. Neophilia, assessed as exploration of a novel object placed in the arena, among others, related to the volume of the caudate nucleus.ConclusionIn summary, our data suggest a prominent role of temporal structures (including the hippocampus) for learning capability, as well as thalamic and anterior cingulate structures for cognitive flexibility and response inhibition. The amygdala, the anterior cingulate lobe, and the caudate nucleus are particularly linked to animal personality in the open-field setting. These findings are congruent with the comparative psychological literature and provide a valuable basis for future studies elucidating aspects of behavioral variation in this nonhuman primate model.

Project description:Parthenogenesis is the biological phenomenon by which embryonic development is initiated without male contribution. Whereas parthenogenesis is a common mode of reproduction in lower organisms, the mammalian parthenote fails to produce a successful pregnancy. We herein describe in vitro parthenogenetic development of monkey (Macaca fascicularis) eggs to the blastocyst stage, and their use to create a pluripotent line of stem cells. These monkey stem cells (Cyno-1 cells) are positive for telomerase activity and are immunoreactive for alkaline phosphatase, octamer-binding transcription factor 4 (Oct-4), stage-specific embryonic antigen 4 (SSEA-4), tumor rejection antigen 1-60 (TRA 1-60), and tumor rejection antigen 1-81 (TRA 1-81) (traditional markers of human embryonic stem cells). They have a normal chromosome karyotype (40 + 2) and can be maintained in vitro in an undifferentiated state for extended periods of time. Cyno-1 cells can be differentiated in vitro into dopaminergic and serotonergic neurons, contractile cardiomyocyte-like cells, smooth muscle, ciliated epithelia, and adipocytes. When Cyno-1 cells were injected into severe combined immunodeficient mice, teratomas with derivatives from all three embryonic germ layers were obtained. When grown on fibronectin/laminin-coated plates and in neural progenitor medium, Cyno-1 cells assume a neural precursor phenotype (immunoreactive for nestin). However, these cells remain proliferative and express no functional ion channels. When transferred to differentiation conditions, the nestin-positive precursors assume neuronal and epithelial morphologies. Over time, these cells acquire electrophysiological characteristics of functional neurons (appearance of tetrodotoxin-sensitive, voltage-dependent sodium channels). These results suggest that stem cells derived from the parthenogenetically activated nonhuman primate egg provide a potential source for autologous cell therapy in the female and bypass the need for creating a competent embryo.

Project description:UNLABELLED:Longitudinal sampling for intestinal microbiota in wild animals is difficult, leading to a lack of information on bacterial dynamics occurring in nature. We studied how the composition of microbiota communities changed temporally in free-ranging small primates, rufous mouse lemurs (Microcebus rufus). We marked and recaptured mouse lemurs during their mating season in Ranomafana National Park in southeastern mountainous rainforests of Madagascar for 2 years and determined the fecal microbiota compositions of these mouse lemurs with MiSeq sequencing. We collected 160 fecal samples from 71 animals and had two or more samples from 39 individuals. We found small, but statistically significant, effects of site and age on microbiota richness and diversity and effects of sex, year, and site on microbiota composition, while the within-year temporal trends were less clear. Within-host microbiota showed pervasive variation in intestinal bacterial community composition, especially during the second study year. We hypothesize that the biological properties of mouse lemurs, including their small body size and fast metabolism, may contribute to the temporal intraindividual-level variation, something that should be testable with more-extensive sampling regimes. IMPORTANCE:While microbiome research has blossomed in recent years, there is a lack of longitudinal studies on microbiome dynamics on free-ranging hosts. To fill this gap, we followed mouse lemurs, which are small heterothermic primates, for 2 years. Most studied animals have shown microbiota to be stable over the life span of host individuals, but some previous research also found ample within-host variation in microbiota composition. Our study used a larger sample size than previous studies and a study setting well suited to track within-host variation in free-ranging mammals. Despite the overall microbiota stability at the population level, the microbiota of individual mouse lemurs can show large-scale changes in composition in time periods as short as 2 days, suggesting caution in inferring individual-level patterns from population-level data.

Dataset Information

Survey of Drug Oxidation Activities in Hepatic and Intestinal Microsomes of Individual Common Marmosets, a New Nonhuman Primate Animal Model.

Publications

Survey of Drug Oxidation Activities in Hepatic and Intestinal Microsomes of Individual Common Marmosets, a New Nonhuman Primate Animal Model.

Similar Datasets

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