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M Axelstad Technical University of Denmark, National Food Institute, Kongens Lyngby, Denmark

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U Hass Technical University of Denmark, National Food Institute, Kongens Lyngby, Denmark

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M Scholze Brunel University, Uxbridge, UK

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S Christiansen Technical University of Denmark, National Food Institute, Kongens Lyngby, Denmark

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A Kortenkamp Brunel University, Uxbridge, UK

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J Boberg Technical University of Denmark, National Food Institute, Kongens Lyngby, Denmark

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Human semen quality is declining in many parts of the world, but the causes are ill defined. In rodents, impaired sperm production can be seen with early life exposure to certain endocrine-disrupting chemicals, but the effects of combined exposures are not properly investigated. In this study, we examined the effects of early exposure to the painkiller paracetamol and mixtures of human relevant endocrine-disrupting chemicals in rats. One mixture contained four estrogenic compounds; another contained eight anti-androgenic environmental chemicals and a third mixture contained estrogens, anti-androgens and paracetamol. All exposures were administered by oral gavage to time-mated Wistar dams rats (n = 16–20) throughout gestation and lactation. In the postnatal period, testicular histology was affected by the total mixture, and at the end of weaning, male testis weights were significantly increased by paracetamol and the high doses of the total and the anti-androgenic mixture, compared to controls. In all dose groups, epididymal sperm counts were reduced several months after end of exposure, i.e. at 10 months of age. Interestingly, the same pattern of effects was seen for paracetamol as for mixtures with diverse modes of action. Reduced sperm count was seen at a dose level reflecting human therapeutic exposure to paracetamol. Environmental chemical mixtures affected sperm count at the lowest mixture dose indicating an insufficient margin of safety for the most exposed humans. This causes concern for exposure of pregnant women to paracetamol as well as environmental endocrine disrupters.

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Daniel Alexander Hescheler Department of Nuclear Medicine, University Hospital Münster, Münster, Germany
European Institute for Molecular Imaging (EIMI), University of Münster, Münster, Germany

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Milan Janis Michael Hartmann Department of General, Visceral, Tumor and Transplant Surgery, University Hospital Cologne, Cologne, Germany

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Burkhard Riemann Department of Nuclear Medicine, University Hospital Münster, Münster, Germany

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Maximilian Michel Institute of Zoology, University of Cologne Germany, Cologne, Germany

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Christiane Josephine Bruns Department of General, Visceral, Tumor and Transplant Surgery, University Hospital Cologne, Cologne, Germany

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Hakan Alakus Department of General, Visceral, Tumor and Transplant Surgery, University Hospital Cologne, Cologne, Germany

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Costanza Chiapponi Department of General, Visceral, Tumor and Transplant Surgery, University Hospital Cologne, Cologne, Germany

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Objective

Anaplastic thyroid cancer (ATC) is one of the most lethal human cancers with meager treatment options. We aimed to identify the targeted drugs already approved by the Food and Drug Administration (FDA) for solid cancer in general, which could be effective in ATC.

Design

Database mining.

Methods

FDA-approved drugs for targeted therapy were identified by screening the databases of MyCancerGenome and the National Cancer Institute. Drugs were linked to the target genes by querying Drugbank. Subsequently, MyCancerGenome, CIViC, TARGET and OncoKB were mined for genetic alterations which are predicted to lead to drug sensitivity or resistance. We searched the Cancer Genome Atlas database (TCGA) for patients with ATC and probed their sequencing data for genetic alterations which predict a drug response.

Results

In the study,155 FDA-approved drugs with 136 potentially targetable genes were identified. Seventeen (52%) of 33 patients found in TCGA had at least one genetic alteration in targetable genes. The point mutation BRAF V600E was seen in 45% of patients. PIK3CA occurred in 18% of cases. Amplifications of ALK and SRC were detected in 3% of cases, respectively. Fifteen percent of the patients displayed a co-mutation of BRAF and PIK3CA. Besides BRAF-inhibitors, the PIK3CA-inhibitor copanlisib showed a genetically predicted response. The 146 (94%) remaining drugs showed no or low (under 4% cases) genetically predicted drug response.

Conclusions

While ATC carrying BRAF mutations can benefit from BRAF inhibitors and this effect might be enhanced by a combined strategy including PIK3CA inhibitors in some of the patients, alterations in BRAFWT ATC are not directly targeted by currently FDA-approved options.

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Bernardo Maia Neuroendocrinology Research Center/Endocrinology Division – Medical School and Hospital Universitário Clementino Fraga Filho – Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

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Leandro Kasuki Neuroendocrinology Research Center/Endocrinology Division – Medical School and Hospital Universitário Clementino Fraga Filho – Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
Neuroendocrinology Division – Instituto Estadual do Cérebro Paulo Niemeyer, Rio de Janeiro, Brazil
Endocrinology Division – Hospital Federal de Bonsucesso, Rio de Janeiro Brazil

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Mônica R Gadelha Neuroendocrinology Research Center/Endocrinology Division – Medical School and Hospital Universitário Clementino Fraga Filho – Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
Neuroendocrinology Division – Instituto Estadual do Cérebro Paulo Niemeyer, Rio de Janeiro, Brazil
Neuropatology and Molecular Genetics Laboratory – Instituto Estadual do Cérebro Paulo Niemeyer, Rio de Janeiro, Brazil

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Acromegaly is a systemic disease associated with increased morbidity and mortality. Most of these comorbidities can be prevented or delayed with adequate disease treatment. Although three modalities of treatment (surgery, medical treatment, and radiotherapy) are available and new drugs were approved in the last decades, there are still some patients that maintain disease activity despite treatment. Therefore, there is a need for novel therapies for acromegaly and for that purpose new formulations of currently used drugs and also new drugs are currently under study. In this review, we summarize the novel therapies for acromegaly.

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Zhenyu Liu Z Liu, Beijing Luhe Hospital, Beijing, 101199, China

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Huixi Kong H Kong, Beijing Shijitan Hospital Capital Medical University, Beijing, China

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Baoyu Zhang B Zhang, Beijing Luhe Hospital, Beijing, 101117, China

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To optimize the treatment plan for patients with type 2 diabetes mellitus (T2DM) and hyperuricemia, this narrative literature review summarizes the effect of antidiabetic drugs on serum uric acid (SUA) levels using data from observational studies, prospective clinical trials, post-hoc analyses and meta‐analyses. SUA is an independent risk factor for T2DM, and evidence has shown that patients with both gout and T2DM exhibit a mutually interdependent effect on higher incidences. We find that insulin and dipeptidyl peptidase 4 inhibitor (DPP-4i) except linagliptin could increase the SUA, and other drugs including metformin, thiazolidinediones (TZDs), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), linagliptin, sodium-glucose cotransporter 2 inhibitors (SGLT2i) and α-glucosidase inhibitors have a reduction effect on SUA. We explain the mechanisms of different antidiabetic drugs above on SUA and analyze them compared with actual data. For sulfonylureas, meglitinides, and amylin analogs, the underlying mechanism remains unclear. We think the usage of linagliptin and SGLT2i is the most potentially effective treatment of patients with T2DM and hyperuricemia currently. Our review is a comprehensive summary of the effects of antidiabetic drugs on SUA, which includes actual data, the mechanisms of SUA regulation, and the usage rate of drugs.

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Nassim Ghaffari-Tabrizi-Wizsy Otto Loewi Research Center – Immunology and Pathophysiology, Medical University of Graz, Graz, Austria

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Christina Angelika Passegger Otto Loewi Research Center – Immunology and Pathophysiology, Medical University of Graz, Graz, Austria

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Laura Nebel Otto Loewi Research Center – Immunology and Pathophysiology, Medical University of Graz, Graz, Austria

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Fabian Krismer Otto Loewi Research Center – Immunology and Pathophysiology, Medical University of Graz, Graz, Austria

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Gudrun Herzer-Schneidhofer Otto Loewi Research Center – Immunology and Pathophysiology, Medical University of Graz, Graz, Austria

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Gert Schwach Otto Loewi Research Center – Immunology and Pathophysiology, Medical University of Graz, Graz, Austria

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Roswitha Pfragner Otto Loewi Research Center – Immunology and Pathophysiology, Medical University of Graz, Graz, Austria

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Preclinical trials of medullary thyroid cancer (MTC) therapeutics require both in vitro and in vivo analyses. Human tumour xenografted rodent models, which are considered the ‘gold standard’ to study and validate the efficacy and toxicity of lead compounds before translation to clinical trials, are very expensive, subject to organismal variability and ethical controversies. The avian chorioallantoic membrane (CAM) assay provides an alternative versatile, cost-effective and ethically less objectionable short-term, in vivo model for reliable screening of drugs. In this work, we grafted two MTC cell lines and patient-derived MTC tumour samples onto the avian CAM and characterised the resulted tumours histologically and immunohistochemically. Our findings provide the evidence that the CAM assay is a suitable model for studying the pathophysiology of MTC and can even be used as in vivo system for drug testing.

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Ruixin Hu School of pharmacy, Qing Dao University, Qingdao, China

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Yanting Yuan School of pharmacy, Qing Dao University, Qingdao, China

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Chaolong Liu School of pharmacy, Qing Dao University, Qingdao, China

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Ji Zhou School of pharmacy, Qing Dao University, Qingdao, China

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Lixia Ji School of pharmacy, Qing Dao University, Qingdao, China

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Guohui Jiang School of pharmacy, Qing Dao University, Qingdao, China

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In patients with type 2 diabetes mellitus (T2DM), the intestinal flora is out of balance and accompanied by leaky gut. The flora is characterized by an increase in mucus-degrading bacteria and a decrease in fiber-degrading bacteria. Short-chain fatty acids (SCFAs), as the major fiber-degrading bacteria fermentation, not only ameliorate the leaky gut, but also activate GPR43 to increase the mass of functional pancreatic β-cells and exert anti-inflammation effect. At present, the gut microbiota is considered as the potential target for anti-diabetes drugs, and how to reverse the imbalance of gut microbiota has become a therapeutic strategy for T2DM. This review briefly summarizes the drugs or compounds that have direct or potential therapeutic effects on T2DM by modulating the gut microbiota, including biguanides, isoquinoline alkaloids, stilbene and C7N-aminocyclic alcohols.

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Maria Cristina De Martino Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
Dipartimento di Medicina Clinica e Chirurgia, Università Federico II, Naples, Italy

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Richard A Feelders Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands

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Claudia Pivonello Dipartimento di Medicina Clinica e Chirurgia, Università Federico II, Naples, Italy

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Chiara Simeoli Dipartimento di Medicina Clinica e Chirurgia, Università Federico II, Naples, Italy

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Fortuna Papa Dipartimento di Medicina Clinica e Chirurgia, Università Federico II, Naples, Italy

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Annamaria Colao Dipartimento di Medicina Clinica e Chirurgia, Università Federico II, Naples, Italy

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Rosario Pivonello Dipartimento di Medicina Clinica e Chirurgia, Università Federico II, Naples, Italy

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Leo J Hofland Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands

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Adrenocortical carcinomas (ACCs) are rare tumors with scant treatment options for which new treatments are required. The mTOR pathway mediates the intracellular signals of several growth factors, including the insulin-like growth factors (IGFs), and therefore represents a potential attractive pathway for the treatment of several malignancies including ACCs. Several mTOR inhibitors, including sirolimus, temsirolimus and everolimus, have been clinically developed. This review summarizes the results of the studies evaluating the expression of the mTOR pathway components in ACCs, the effects of the mTOR inhibitors alone or in combination with other drugs in preclinical models of ACCs and the early experience with the use of these compounds in the clinical setting. The mTOR pathway seems a potential target for treatment of patients with ACC, but further investigation is still required to define the potential role of mTOR inhibitors alone or in combination with other drugs in the treatment of ACC patients.

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Anne Jouinot Department of Medical Oncology, Cochin Hospital, Paris Descartes University, CARPEM, AP-HP, Paris, France
Institut Cochin, INSERM U1016, CNRS UMR8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France

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Bernard Royer CHU Besançon, Clinical Pharmacology and Toxicology Dpt, Besançon cedex, France

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Etienne Chatelut Institut Claudius-Regaud, Université de Toulouse, INSERM, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France

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Sotheara Moeung Institut Claudius-Regaud, Université de Toulouse, INSERM, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France

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Guillaume Assié Institut Cochin, INSERM U1016, CNRS UMR8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
Department of Endocrinology, Center for Rare Adrenal Diseases, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France

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Audrey Thomas-Schoemann Department of Pharmacy, Cochin Hospital, Paris Descartes University, AP-HP, Paris, France
Pharmacokinetics and Pharmacochemistry Unit, Cochin Hospital, Paris Descartes University, AP-HP, Paris, France

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Jérôme Bertherat Institut Cochin, INSERM U1016, CNRS UMR8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
Department of Endocrinology, Center for Rare Adrenal Diseases, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France

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François Goldwasser Department of Medical Oncology, Cochin Hospital, Paris Descartes University, CARPEM, AP-HP, Paris, France

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Benoit Blanchet Pharmacokinetics and Pharmacochemistry Unit, Cochin Hospital, Paris Descartes University, AP-HP, Paris, France
UMR8638 CNRS, Pharmacy UFR, University of Paris Descartes, PRES sorbonne Paris Cité, Paris, France

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Background

The combination of mitotane and platinum-etoposide chemotherapy is a front-line treatment in metastatic adrenocortical carcinoma (ACC), although this regimen shows limited efficacy. Pharmacokinetic drug–drug interaction between mitotane, a strong CYP3A4 inducer, and etoposide, which is a substrate of CYP3A4, may contribute to chemoresistance. The aim of this pilot study was to assess the pharmacokinetic interaction between mitotane and etoposide in ACC patients.

Methods

Five consecutive ACC patients treated with platinum etoposide (120–150 mg/m2 day 1–2–3 at cycle 1), with or without concomitant mitotane, were included. In the absence of limiting toxicity, a dose escalation of etoposide was proposed since cycle 2. Plasma etoposide concentrations were measured using liquid chromatography at 0, 4 and 24 h after each infusion. Clearance and area under the curve (AUC) of etoposide were determined at each cycle.

Results

Patients received two to six chemotherapy cycles, in association with mitotane (N = 4) or after mitotane discontinuation (N = 1). Etoposide clearance was two-fold higher with concomitant mitotane (4.95 L/h) than after mitotane discontinuation (2.53 L/h, P = 0.014), and 2.5-fold higher than that in reference population not treated with mitotane (1.81 L/h). Etoposide dose escalation was performed in four patients under mitotane, resulting in two minor tumor responses and one severe toxicity (febrile aplasia) at dose of 300 mg/m2/day. Tumor response was associated with higher etoposide AUC (267.3 vs 188.8 mg.h/L, P = 0.04).

Conclusion

A drug–drug interaction between mitotane and etoposide may contribute to the low efficacy of platinum-etoposide chemotherapy. This pilot study suggests further a potential benefit of increasing etoposide dose in ACC patients receiving mitotane.

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Jean-Benoît Corcuff Department of Nuclear Medicine, Haut Lévêque Hospital, Pessac, France
Nutrition et Neurobiologie intégrée, UMR 1286, University of Bordeaux, Bordeaux, France
Groupe de Biologie Spécialisée, Société Française de Médecine Nucléaire, Paris, France

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Laurence Chardon Department of Biochemistry, Edouard Herriot Hospital, Lyon, France

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Ines El Hajji Ridah Biomnis, Lyon, France

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Julie Brossaud Department of Nuclear Medicine, Haut Lévêque Hospital, Pessac, France
Nutrition et Neurobiologie intégrée, UMR 1286, University of Bordeaux, Bordeaux, France
Groupe de Biologie Spécialisée, Société Française de Médecine Nucléaire, Paris, France

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Context

Biogenic amines such as 5-hydroxy-indole acetic acid (5HIAA) the main metabolite of serotonin or metanephrines (catecholamines metabolites) are used as biomarkers of neuroendocrine tumours.

Objective

To re-evaluate the recommendations for urinary sampling (preservatives, diet, drugs, etc.) as many of the reported analytical interferences supporting these recommendations are related to obsolete assays.

Methods

Bibliographic analysis of old and modern assays concerning preservation, extraction, assay and interferences.

Results

5HIAA may degrade as soon as urine is excreted. Thus, acids as preservatives (hydrochloric or acetic acid) have to be immediately added. Care should be taken not to decrease the pH under 2. Urine preservative for metanephrine assays is not mandatory. Diets including serotonin-, tryptophan- and dopamine-rich foods have to be avoided depending on the biomarkers investigated (bananas, plantain, nuts, etc.). Tryptophan-rich over-the-counter formulas have to be prohibited when 5HIAA has to be assayed. Acetaminophen may interfere with electrochemical detection depending on high-pressure liquid chromatography (HPLC) parameters. No interference is known with mass spectrometric assays but with the one described for metanephrines determination. Some drugs interfere however with serotonin and catecholamines secretion and/or metabolism (monoamine oxidase inhibitors, serotonin or dopamine recapture inhibitors, etc.).

Conclusion

Revisited recommendations are provided for the diet, the drugs and the preservatives before HPLC coupled with electrochemical and mass spectrometry assays.

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Sarmistha Banerjee Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA

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Allison M Hayes Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA

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Bernard H Shapiro Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA

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The sexually dimorphic expression of cytochromes P450 (CYP) drug metabolizing enzymes has been reported in all species examined. These sex differences are initially expressed during puberty and are solely regulated by sex differences in the circulating growth hormone (GH) profiles. Once established, however, the different male- and female-dependent CYP isoforms are permanent and immutable, suggesting that adult CYP expression requires imprinting. Since the hormone that regulates an adult function is likely the same hormone that imprints the function, we selectively blocked GH secretion in some newborn male rats while others also received a concurrent physiologic replacement of rat GH. Rats were subsequently challenged, peripubertally, with either a masculine-like episodic GH regimen or the GH vehicle alone. The results demonstrate that episodic GH regulation of male-specific CYP2C11 and CYP3A2, as well as female-predominant CYP2C6, are dependent on developmental GH imprinting. Moreover, the induction and/or activation of major components in the signal transduction pathway regulating the expression of the principal CYP2C11 isoform is obligatorily dependent on perinatal GH imprinting without which CYP2C11 and drug metabolism would be permanently and profoundly suppressed. Since there are additional adult metabolic functions also regulated by GH, pediatric drug therapy that is known to disrupt GH secretion could unintentionally impair adult health.

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