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Impaired hepatic drug and steroid metabolism in congenital adrenal hyperplasia due to P450 oxidoreductase deficiency

OBJECTIVE: Patients with congenital adrenal hyperplasia due to P450 oxidoreductase (POR) deficiency (ORD) present with disordered sex development and glucocorticoid deficiency. This is due to disruption of electron transfer from mutant POR to microsomal cytochrome P450 (CYP) enzymes that play a key...

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Autores principales: Tomalik-Scharte, Dorota, Maiter, Dominique, Kirchheiner, Julia, Ivison, Hannah E, Fuhr, Uwe, Arlt, Wiebke
Formato: Texto
Lenguaje:English
Publicado: BioScientifica 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2977993/
https://www.ncbi.nlm.nih.gov/pubmed/20844025
http://dx.doi.org/10.1530/EJE-10-0764
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author Tomalik-Scharte, Dorota
Maiter, Dominique
Kirchheiner, Julia
Ivison, Hannah E
Fuhr, Uwe
Arlt, Wiebke
author_facet Tomalik-Scharte, Dorota
Maiter, Dominique
Kirchheiner, Julia
Ivison, Hannah E
Fuhr, Uwe
Arlt, Wiebke
author_sort Tomalik-Scharte, Dorota
collection PubMed
description OBJECTIVE: Patients with congenital adrenal hyperplasia due to P450 oxidoreductase (POR) deficiency (ORD) present with disordered sex development and glucocorticoid deficiency. This is due to disruption of electron transfer from mutant POR to microsomal cytochrome P450 (CYP) enzymes that play a key role in glucocorticoid and sex steroid synthesis. POR also transfers electrons to all major drug-metabolizing CYP enzymes, including CYP3A4 that inactivates glucocorticoid and oestrogens. However, whether ORD results in impairment of in vivo drug metabolism has never been studied. DESIGN: We studied an adult patient with ORD due to homozygous POR A287P, the most frequent POR mutation in Caucasians, and her clinically unaffected, heterozygous mother. The patient had received standard dose oestrogen replacement from 17 until 37 years of age when it was stopped after she developed breast cancer. METHODS: Both subjects underwent in vivo cocktail phenotyping comprising the oral administration of caffeine, tolbutamide, omeprazole, dextromethorphan hydrobromide and midazolam to assess the five major drug-metabolizing CYP enzymes. We also performed genotyping for variant CYP alleles known to affect drug metabolism. RESULTS: Though CYP enzyme genotyping predicted normal or high enzymatic activities in both subjects, in vivo assessment showed subnormal activities of CYP1A2, CYP2C9, CYP2D6 and CYP3A4 in the patient and of CYP1A2 and CYP2C9 in her mother. CONCLUSIONS: Our results provide in vivo evidence for an important role of POR in regulating drug metabolism and detoxification. In patients with ORD, in vivo assessment of drug-metabolizing activities with subsequent tailoring of drug therapy and steroid replacement should be considered.
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spelling pubmed-29779932010-12-01 Impaired hepatic drug and steroid metabolism in congenital adrenal hyperplasia due to P450 oxidoreductase deficiency Tomalik-Scharte, Dorota Maiter, Dominique Kirchheiner, Julia Ivison, Hannah E Fuhr, Uwe Arlt, Wiebke Eur J Endocrinol Clinical Study OBJECTIVE: Patients with congenital adrenal hyperplasia due to P450 oxidoreductase (POR) deficiency (ORD) present with disordered sex development and glucocorticoid deficiency. This is due to disruption of electron transfer from mutant POR to microsomal cytochrome P450 (CYP) enzymes that play a key role in glucocorticoid and sex steroid synthesis. POR also transfers electrons to all major drug-metabolizing CYP enzymes, including CYP3A4 that inactivates glucocorticoid and oestrogens. However, whether ORD results in impairment of in vivo drug metabolism has never been studied. DESIGN: We studied an adult patient with ORD due to homozygous POR A287P, the most frequent POR mutation in Caucasians, and her clinically unaffected, heterozygous mother. The patient had received standard dose oestrogen replacement from 17 until 37 years of age when it was stopped after she developed breast cancer. METHODS: Both subjects underwent in vivo cocktail phenotyping comprising the oral administration of caffeine, tolbutamide, omeprazole, dextromethorphan hydrobromide and midazolam to assess the five major drug-metabolizing CYP enzymes. We also performed genotyping for variant CYP alleles known to affect drug metabolism. RESULTS: Though CYP enzyme genotyping predicted normal or high enzymatic activities in both subjects, in vivo assessment showed subnormal activities of CYP1A2, CYP2C9, CYP2D6 and CYP3A4 in the patient and of CYP1A2 and CYP2C9 in her mother. CONCLUSIONS: Our results provide in vivo evidence for an important role of POR in regulating drug metabolism and detoxification. In patients with ORD, in vivo assessment of drug-metabolizing activities with subsequent tailoring of drug therapy and steroid replacement should be considered. BioScientifica 2010-12 /pmc/articles/PMC2977993/ /pubmed/20844025 http://dx.doi.org/10.1530/EJE-10-0764 Text en © 2010 European Society of Endocrinology http://www.bioscientifica.com/journals/reuselicenceeje/ This is an Open Access article distributed under the terms of the European Journal of Endocrinology's Re-use Licence (http://www.bioscientifica.com/journals/reuselicenceeje/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Clinical Study
Tomalik-Scharte, Dorota
Maiter, Dominique
Kirchheiner, Julia
Ivison, Hannah E
Fuhr, Uwe
Arlt, Wiebke
Impaired hepatic drug and steroid metabolism in congenital adrenal hyperplasia due to P450 oxidoreductase deficiency
title Impaired hepatic drug and steroid metabolism in congenital adrenal hyperplasia due to P450 oxidoreductase deficiency
title_full Impaired hepatic drug and steroid metabolism in congenital adrenal hyperplasia due to P450 oxidoreductase deficiency
title_fullStr Impaired hepatic drug and steroid metabolism in congenital adrenal hyperplasia due to P450 oxidoreductase deficiency
title_full_unstemmed Impaired hepatic drug and steroid metabolism in congenital adrenal hyperplasia due to P450 oxidoreductase deficiency
title_short Impaired hepatic drug and steroid metabolism in congenital adrenal hyperplasia due to P450 oxidoreductase deficiency
title_sort impaired hepatic drug and steroid metabolism in congenital adrenal hyperplasia due to p450 oxidoreductase deficiency
topic Clinical Study
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2977993/
https://www.ncbi.nlm.nih.gov/pubmed/20844025
http://dx.doi.org/10.1530/EJE-10-0764
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