Mice predict the effectiveness of orally taken drugs
The amount of an orally taken drug that makes it to the site in the body at which it exerts its effects is much lower than the amount of an intravenously administered drug and it varies considerably between individuals. One reason for this is that a substantial proportion of more than half of all orally prescribed medications are broken down in the intestine and liver, by an enzyme known as CYP3A, before reaching their site of action (a process known as first-pass metabolism). In a new study, Alfred Schinkel and colleagues from The Netherlands Cancer Institute, have developed a new mouse model for predicting the loss in available drug due to metabolism by CYP3A.
In the study, mice lacking all 8 genes encoding functional mouse CYP3A proteins (Cyp3A-/- mice) were generated and the anticancer chemotherapeutic agent docetaxol was found to accumulate in the tissues of these mice at much higher levels than in normal mice. Engineering Cyp3A-/- mice to express human CYP3A in the intestine dramatically decreased the absorption of orally administered docetaxol into the blood. By contrast, Cyp3A-/- mice engineered to express human CYP3A in the liver showed only a slight decrease in the amount of orally administered docetaxol reaching the blood. These data indicate a key role for CYP3A in the intestine as a mediator of first-pass metabolism and led the authors to suggest that these mice provide a powerful tool to help predict whether drugs being developed will work effectively if given orally. In an accompanying commentary Kenneth Thummel from the University of Washington, Seattle, expands on the usefulness of these mice as tools for drug development and discusses how these data might explain interpatient variability in first-pass metabolism.
TITLE: New models for understanding the role of cytochrome P450 3A in xenobiotic metabolism
AUTHOR CONTACT:
Alfred H. Schinkel
The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Phone: 31-20-5122046; Fax: 31-20-5122050; E-mail: a.schinkel@nki.nl.
View the PDF of this article at: https://www.the-jci.org/article.php?id=33435
ACCOMPANYING COMMENTARY
TITLE: Gut instincts: CYP3A4 and intestinal drug metabolism
AUTHOR CONTACT:
Kenneth E. Thummel
University of Washington, Seattle, Washington, USA.
Phone: (206) 543-0819; Fax: (206) 543-3204; Email: Thummel@u.washington.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=34007
EDITOR'S PICK: Stressed out skin loses its antimicrobial defense mechanism
It is well known that being stressed increases our susceptibility to infections by impairing the function of our immune system, but the molecular links between stress and diminished immune function have not been determined. However, Peter Elias and colleagues at UCSF, have now characterized a mechanistic link in mice between psychological stress and increased susceptibility to skin infections.
Mice subjected to conditions of psychological stress were found to be more susceptible to group A Streptococcus pyogenes skin infections than mice housed under normal conditions. This was associated with decreased expression of antimicrobial peptides by the epidermis of the skin. Further analysis revealed that psychological stress induced the increased production of glucocorticoids and that this inhibited the synthesis of fats in the epidermis of the skin and decreased the secretion of vesicles that contain antimicrobial peptides. As indicated by the authors and Andrzej Slominski from the University of Tennessee, Memphis, in an accompanying commentary, these data lead to the suggestion that the immune function of the skin might be improved in individuals who are stressed by inhibiting the action of glucocorticoids.
TITLE: Psychological stress downregulates epidermal antimicrobial peptide expression and increases severity of cutaneous infections in mice
AUTHOR CONTACT:
Peter M. Elias
Veterans Affairs Medical Center, University of California at San Francisco, San Francisco, California, USA.
Phone: (415) 750-2091; Fax: (415) 751-3927; E-mail: eliasp@derm.ucsf.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=31726
ACCOMPANYING COMMENTARY
TITLE: A nervous breakdown in the skin: Stress and the epidermal barrier
AUTHOR CONTACT:
Andrzej Slominski
University of Tennessee, Memphis, Tennessee, USA.
Phone: (901) 448-3741; Fax: (901) 448-6979; Email: aslominski@utmem.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=33508
EDITOR'S PICK: The chemical peroxynitrite tolerates pain
The repeated use of opiate drugs such as morphine to relieve chronic pain results in individuals having to take higher and higher doses of the drug to achieve equivalent pain relief (they are said to exhibit antinociceptive tolerance). The molecular reasons for antinociceptive tolerance are not well defined. However, a new study by Daniela Salvemini and colleagues at Saint Louis University School of Medicine, has identified a crucial role for the chemical peroxynitrite (ONOO-) in this process in mice. These results led the authors and Gavril Pasternak from the Memorial Sloan-Kettering Cancer Center, New York, in an accompanying commentary, to suggest that the development of drugs targeting ONOO- might provide an adjunct therapy for individuals using opiates to relieve chronic pain.
Antinociceptive tolerance in mice repeatedly administered morphine was associated with the accumulation of tyrosine-nitrated proteins in the dorsal horn of the spinal cord, increased production of proinflammatory cytokines, oxidative DNA damage, and activation of the nuclear protein poly(ADP-ribose) polymerase. These changes were inhibited, as was the induction of antinociceptive tolerance, if the morphine was administered together with a pharmacological inhibitor of nitric oxide synthesis, a pharmacological scavenger of superoxide, or a pharmacological catalyst for ONOO- decomposition. Together, these data indicate that ONOO- has a crucial role in the development of morphine-induced antinociceptive tolerance in mice.
TITLE: Therapeutic manipulation of peroxynitrite attenuates the development of opiate-induced antinociceptive tolerance in mice
AUTHOR CONTACT:
Daniela Salvemini
Saint Louis University School of Medicine, St. Louis, Missouri, USA.
Phone: (314) 577-8856; Fax: (314) 577-8859; E-mail: salvemd@slu.edu.
MEDIA CONTACT:
Donn Walker,
Saint Louis University School of Medicine, St. Louis, Missouri, USA.
Phone: (314) 977-8015; E-mail: dwalke18@slu.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=32420
ACCOMPANYING COMMENTARY
TITLE: When it comes to opiates, just say NO
AUTHOR CONTACT:
Gavril W. Pasternak
Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Phone: (646) 888-2165; Email: pasterng@mskcc.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=34035
OPHTHALMOLOGY: Macrophages are not all seeing in the eye
Age-related macular degeneration (AMD) is the leading cause of blindness in adults over the age of 50. AMD is characterized by abnormal angiogenesis (the growth of new blood vessels) under the retina. New research using mice by Rajendra S. Apte and colleagues at Washington University School of Medicine, St. Louis, has indicated that as immune cells known as macrophages age they lose their ability to inhibit injury-induced abnormal angiogenesis in the eye.
In the study, macrophages from old mice injected into the eye of mice in which damage to the eye had been induced by exposure to a laser were unable to prevent abnormal angiogenesis. By contrast, macrophages from young mice substantially blocked the abnormal angiogenesis. Further analysis showed that following laser-induced injury to the eye, ocular macrophages from old mice expressed less FasL, TNF-alpha, and IL-12, as well as more IL-10, than those from young mice. The authors therefore suggested that a decrease in macrophage antiangiogenic function upon aging might explain why individuals over 50 years of age are more susceptible to AMD and other diseases associated with abnormal angiogenesis, such as cancer. The broader significance of this study is discussed in the accompanying commentary by Martine Jager and Caroline Claver.
TITLE: Senescence regulates macrophage activation and angiogenic fate at sites of tissue injury in mice
AUTHOR CONTACT:
Rajendra S. Apte
Washington University School of Medicine, St. Louis, Missouri, USA.
Phone: (314) 747-5262; Fax: (314) 362-6793; E-mail: apte@vision.wustl.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=32430
ACCOMPANYING COMMENTARY
TITLE: Macrophages feel their age in macular degeneration
AUTHOR CONTACT:
Martine J. Jager
Leiden University Medical Center, Leiden, The Netherlands.
Phone: 31-71-5263097; Fax: 31-71-5248222; Email: m.j.jager@lumc.nl.
View the PDF of this article at: https://www.the-jci.org/article.php?id=34070
IMMUNOLOGY: What immune cells see: the ins and outs of peptide processing
Immune cells known as T cells help us clear invading microbes, such as HIV, from our bodies, but they can also cause autoimmunity when they inappropriately attack our own tissues. T cells are activated when a receptor on their surface (the TCR) recognizes a specific complex of a peptide fragment bound to a protein known as an MHC molecule. Defining the peptides identified by T cells mediating autoimmunity and immune responses against invading microbes, as well as harnessing this information for the design of therapeutics and vaccines, is an area of intensive investigation. New insight into these matters is provided in the November issue of the Journal of Clinical Investigation by two studies that report technical advances in the field. The clinical implications of these are discussed in an accompanying commentary by Luc Teyton from The Scripps Research Institute, La Jolla.
Wahlstrom and colleagues from the Karolinska University Hospital, Sweden, developed a strategy to determine the peptide fragments bound by human MHC molecules activating inappropriate immune responses in vivo. Using this approach they identified 78 peptide fragments bound to the MHC molecule HLA-DR on cells isolated from the lungs of patients with sarcoidosis, an inflammatory disease of the lungs mediated largely by CD4+ T cells. The authors suggest that this approach might be used to identify the peptides recognized by autoreactive T cells that attack the body to cause diseases such as diabetes and rheumatoid arthritis, information that could lead to the development of new treatment strategies.
By contrast, Le Gall and colleagues from Massachusetts General Hospital and Harvard Medical School, Boston, have provided insight into the peptides recognized by CD8+ T cells fighting infection with HIV. The main peptide fragment of the HIV-1 protein Gag that binds the human MHC molecule HLA-A3 is known as the immunodominant epitope. In vitro assays determined that the amino acid sequence flanking the immunodominant epitope caused the immunodominance as moving these sequences to flank other peptides increased the frequency with which they bound HLA-A3. The authors therefore suggested that these flanking sequences might be used to enhance the effectiveness of HIV vaccines.
TITLE: Identification of HLA-DR -- bound peptides presented by human bronchoalveolar lavage cells in sarcoidosis
AUTHOR CONTACT:
Jan Wahlstrom
Karolinska University Hospital, Stockholm, Sweden.
Phone: 46-8-5177-0663; Fax: 46-8-5177-5451; Email: jan.wahlstrom@ki.se.
MEDIA CONTACT:
Katarina Sternudd
Karolinska University Hospital, Stockholm, Sweden.
Email: katarina.sternudd@ki.se.
View the PDF of this article at: https://www.the-jci.org/article.php?id=32401
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TITLE: Portable flanking sequences modulate CTL epitope processing
AUTHOR CONTACT:
Sylvie Le Gall
Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Phone: (617) 726-1406; Fax: (617) 726-5411; E-mail: sylvie_legall@hms.harvard.edu.
MEDIA CONTACT:
Susan McGreevey
Massachusetts General Hospital, Boston, Massachusetts, USA.
(617) 724-2764; E-mail: smcgreevey@partners.org
David Cameron
Harvard Medical School, Boston, Massachusetts, USA.
Phone: (617) 432-0442; E-mail: david_cameron@hms.harvard.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=32047
ACCOMPANYING COMMENTARY
TITLE: The saga of MHC-bound peptides: a renaissance for antigen presentation?
AUTHOR CONTACT:
Luc Teyton
The Scripps Research Institute, La Jolla, California, USA.
Phone: (858) 784-2728; Fax: (858) 784-8805; Email: lteyton@scripps.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=33997
ONCOLOGY: OX40L helps trigger anti-cancer immune responses
Many researchers are currently trying to develop ways to harness the ability of immune cells known as dendritic cells (DCs) to induce antitumor immune responses as a potential therapeutic approach for the treatment of cancer. New data generated in mice by Toshiaki and colleagues from Tohoku University, Japan, has indicated that expression of a protein known as OX40L is important if DCs are to trigger an antitumor immune response. Dapeng Zhou from the University of Texas MD Anderson Cancer Center, Houston, discusses the therapeutic implications of these data in an accompanying commentary.
In the study, it was shown that DC expression of OX40L was critical if the DCs were to induce antitumor immune responses when injected into mice. Furthermore, if DCs engineered to express high levels of OX40L were injected into pre-established tumors, tumor growth was suppressed by an antitumor immune response mediated by NKT cells and CD4+ Th cells. Further analysis indicated that the intratumoral NKT cells produced high levels of the soluble factor IFN-gamma, leading the authors to suggest that OX40L on DCs might couple innate to adaptive antitumor immunity.
TITLE: OX40 ligand expressed by DCs costimulates NKT and CD4+ Th cell antitumor immunity in mice
AUTHOR CONTACT:
Toshiaki Kikuchi
Tohoku University, Sendai, Japan.
Phone: 81-22-717-8539; Fax: 81-22-717-8549; E-mail: kikuchi@idac.tohoku.ac.jp.
View the PDF of this article at: https://www.the-jci.org/article.php?id=32693
ACCOMPANYING COMMENTARY
TITLE: OX40 signaling directly triggers the antitumor effects of NKT cells
AUTHOR CONTACT:
Dapeng Zhou
University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Phone: (713) 792-3134; Fax: (713) 563-3424; E-mail: dzhou@mdanderson.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=33976
CARDIOLOGY: New insight into heart diseases: coupling blood vessel growth and increased heart size
The heart is able to respond to its surroundings; so, if more power is needed to pump the blood around the body it can increase the size of the muscle cells of the heart (a process known as cardiac hypertrophy). Cardiac hypertrophy can be pathological (i.e. associated with increased morbidity and mortality), such as in individuals with high blood pressure, or physiological (i.e. not associated with impaired heart function), such as in trained athletes. In the November issue of the Journal of Clinical Investigation, two studies in mice provide new insight into the link between cardiac hypertrophy and the growth of new blood vessels (a process known as angiogenesis). As discussed in the accompanying commentary by Kenneth Walsh and Ichiro Shiojima, these reports suggest that cardiac hypertrophy is driven by interactions between heart muscle cells (myocytes) and blood vessel cells (endothelial cells). This challenges the idea that cardiac hypertrophy is myocyte driven and might lead to the development of new therapeutics for the treatment of heat diseases.
In the first study, Jeffery Molkentin and colleagues from Cincinnati Children's Hospital Medical Center, showed that expression of the protein GATA4 in mouse myocytes promotes angiogenesis in the heart under pathological and physiological conditions. The induction of angiogenesis was mediated by upregulation of myocyte expression of VEGF-A, which acted on endothelial cells to promote angiogenesis. As previous studies have indicated that GATA4 activity in the heart is increased by factors that induce hypertrophy, these data show that GATA4 has a central role in inducing the angiogenesis in the heart that is associated with cardiac hypertrophy.
Michael Simons and colleagues from Dartmouth Medical School, Hanover, provided a more direct link between cardiac hypertrophy and angiogenesis in the mouse heart. Expression for 3 weeks in myocytes of the secreted angiogenic growth factor PR39 induced an increase in the mass of blood vessels in the heart. However, if expression was maintained for 6 weeks, the increased angiogenesis was accompanied by cardiac hypertrophy in the absence of pathological stimuli of cardiac hypertrophy. These data indicate that angiogenesis in the normal mouse heart can drive cardiac hypertrophy and further analysis indicated that this process is driven by nitric oxide.
TITLE: Cardiomyocyte GATA4 functions as a stress-responsive regulator of angiogenesis in the murine heart
AUTHOR CONTACT:
Jeffery D. Molkentin
Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Phone: (513) 636-3557; Fax (513)-636-5958; E-mail: jeff.molkentin@cchmc.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=32573
RELATED MANUSCRIPT
TITLE: Myocardial hypertrophy in the absence of external stimuli is induced by angiogenesis in mice
AUTHOR CONTACT:
Michael Simons
Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA.
Phone: (603) 650-3540; Fax: (603) 650-5171; E-mail: michael.simons@dartmouth.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=32024
ACCOMPANYING COMMENTARY
TITLE: Cardiac growth and angiogenesis coordinated by intertissue interactions
AUTHOR CONTACT:
Kenneth Walsh
Boston University School of Medicine, Boston Massachusetts, USA.
Phone: (617) 414-2390; Fax: (617) 414-2391; Email: kxwalsh@bu.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=34126
NEPHROLOGY: I(r)oning out the mechanisms of kidney functions
One of the functions of the kidneys is to maintain an optimal concentration in the body of charged molecules known as ions. Maintaining these at the correct concentration is important for the function of all cells in the body, as well as for maintaining whole body function. For example, the concentration of sodium ions (Na+), which are derived from salt we consume, affects blood pressure -- increased Na+ concentrations increase blood pressure. In the November issue of the Journal of Clinical Investigation, two studies have determined the molecular mechanisms by which the function of two ion transporters primarily expressed in the kidneys are regulated. The commonalities behind these mechanisms and their clinical implications are discussed in the accompanying commentary by Juerg Biber and colleagues at the University of Zurich, Switzerland.
In the first study, David Ellison and colleagues from Oregon Health & Science University, Portland, show that in Xenopus oocytes and human kidney cells, thiazide-sensitive Na-Cl cotransporter (NCC) -- inappropriate activation of which has been recently linked to familial hyperkalemic hypertension (an inherited condition characterized by high blood pressure) -- is regulated by a number of proteins known as WNKs. Interactions between WNK3 and WNK4 were found to fine-tune the function of NCC.
In the second study, Edward Weinman and colleagues from the University of Maryland School of Medicine, Baltimore, showed that in murine and primate kidney cells, Na+-dependent phosphate transporter (Npt2a) was regulated by phosphorylation of serine 77 (S77) of the Npt2a-binding protein sodium-hydrogen exchanger regulatory factor-1 (NHERF-1). Such phosphorylation inhibited phosphate transport in the kidney and was shown to be the mechanism by which the hormone PTH inhibits kidney reabsorption of phosphate.
TITLE: The thiazide-sensitive Na-Cl cotransporter is regulated by a WNK kinase signaling complex
AUTHOR CONTACT:
David H. Ellison
Oregon Health & Science University, Portland, Oregon, USA.
Phone: (503) 494-8490; Fax: (503) 494-5330; E-mail: ellisond@ohsu.edu.
Chao-Ling Yang
Oregon Health & Science University, Portland, Oregon, USA.
Phone: (503) 494-8490; Fax: (503) 494-5330; E-mail: yangch@ohsu.edu
MEDIA CONTACT:
Harry Lenhart
Senior Communications Coordinator
Oregon Health & Science University, Portland, Oregon, USA.
Phone: (503) 494-1360; Fax: (503) 494-8246; E-mail: lenharth@ohsu.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=32033
RELATED MANUSCRIPT
TITLE: Parathyroid hormone inhibits renal phosphate transport by phosphorylation of serine 77 of sodium-hydrogen exchanger regulatory factor–1
AUTHOR CONTACT:
Edward J. Weinman
University of Maryland School of Medicine, Baltimore, Maryland, USA.
Phone: (410) 706-1555; Fax: (410) 706-4195; E-mail: eweinman@medicine.umaryland.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=32738
ACCOMPANYING COMMENTARY
TITLE: Kidney kinase network regulates renal ion cotransport
AUTHOR CONTACT:
Juerg Biber
University of Zurich, Zurich, Switzerland.
Phone: 41-044-635-5032; Fax: 41-044-635-5715; Email: Juerg-Biber@access.uzh.ch.
View the PDF of this article at: https://www.the-jci.org/article.php?id=33859
Journal
Journal of Clinical Investigation