HIV Drug Efavirenz Inhibits CYP21A2 Activity with Possible Clinical Implications.
Adrenal Hyperplasia, Congenital
/ chemically induced
Adult
Alkynes
Benzoxazines
/ administration & dosage
Cell Line
Cyclopropanes
Female
HIV Infections
/ drug therapy
Humans
Infant, Newborn
Pregnancy
Pregnancy Complications, Infectious
/ drug therapy
Premature Birth
/ chemically induced
Prenatal Exposure Delayed Effects
/ chemically induced
Reverse Transcriptase Inhibitors
/ administration & dosage
Steroid 21-Hydroxylase
/ antagonists & inhibitors
21-Hydroxylase deficiency
Adrenal insufficiency
Androgens
Congenital adrenal hyperplasia
Efavirenz
HIV treatment
Neonatal screening
Journal
Hormone research in paediatrics
ISSN: 1663-2826
Titre abrégé: Horm Res Paediatr
Pays: Switzerland
ID NLM: 101525157
Informations de publication
Date de publication:
2019
2019
Historique:
received:
14
01
2019
accepted:
19
04
2019
pubmed:
1
7
2019
medline:
17
1
2020
entrez:
1
7
2019
Statut:
ppublish
Résumé
The HIV drugs lopinavir and ritonavir have recently been reported to cause transient adrenal insufficiency in preterm newborns. We, therefore, considered HIV drugs as a cause of transiently elevated 17-hydroxyprogesterone (17OHP) levels in a neonatal screening test for congenital adrenal hyperplasia in a preterm girl exposed to zidovudine, efavirenz, tenofovir, and emtricitabine. So far, HIV drugs have not been tested for their effect on steroidogenesis and the steroidogenic enzyme activity of CYP21A2 specifically in an in vitro system. We tested the effect of efavirenz, tenofovir, emtricitabine, and zidovudine on steroidogenesis of human adrenal H295R cells. Cells were treated with the drugs at different concentrations including concentrations in therapeutic use. The effect on CYP21A2 activity was assessed by testing the conversion of radiolabeled 17OHP to 11-deoxycortisol. Cell viability was tested by an MTT assay. In addition, recombinant human CYP21A2 protein was used to assess direct drug effects on CYP21A2 activity. We observed significantly decreased CYP21A2 activity in both in vitro testing systems after treatment with efavirenz at therapeutic concentrations. Moreover, efavirenz affected cell viability. By contrast, the other test drugs did not affect steroidogenesis. Follow-up of our patient revealed elevated 17OHP and androgen levels during the first weeks of life, but values normalized spontaneously. Genetic testing for CYP21A2 mutations was negative. Thus, it remains unsettled whether the transient 17OHP elevation in this baby was due to a drug effect. The HIV drug efavirenz inhibits CYP21A2 activity in vitro through direct interaction with enzyme catalysis at therapeutic concentrations. This may have clinical implications for HIV treatment in children and adults. However, so far, clinical data are scarce, and further studies are needed to be able to draw clinical conclusions.
Sections du résumé
BACKGROUND
BACKGROUND
The HIV drugs lopinavir and ritonavir have recently been reported to cause transient adrenal insufficiency in preterm newborns. We, therefore, considered HIV drugs as a cause of transiently elevated 17-hydroxyprogesterone (17OHP) levels in a neonatal screening test for congenital adrenal hyperplasia in a preterm girl exposed to zidovudine, efavirenz, tenofovir, and emtricitabine.
OBJECTIVE
OBJECTIVE
So far, HIV drugs have not been tested for their effect on steroidogenesis and the steroidogenic enzyme activity of CYP21A2 specifically in an in vitro system.
METHODS
METHODS
We tested the effect of efavirenz, tenofovir, emtricitabine, and zidovudine on steroidogenesis of human adrenal H295R cells. Cells were treated with the drugs at different concentrations including concentrations in therapeutic use. The effect on CYP21A2 activity was assessed by testing the conversion of radiolabeled 17OHP to 11-deoxycortisol. Cell viability was tested by an MTT assay. In addition, recombinant human CYP21A2 protein was used to assess direct drug effects on CYP21A2 activity.
RESULTS
RESULTS
We observed significantly decreased CYP21A2 activity in both in vitro testing systems after treatment with efavirenz at therapeutic concentrations. Moreover, efavirenz affected cell viability. By contrast, the other test drugs did not affect steroidogenesis. Follow-up of our patient revealed elevated 17OHP and androgen levels during the first weeks of life, but values normalized spontaneously. Genetic testing for CYP21A2 mutations was negative. Thus, it remains unsettled whether the transient 17OHP elevation in this baby was due to a drug effect.
CONCLUSION
CONCLUSIONS
The HIV drug efavirenz inhibits CYP21A2 activity in vitro through direct interaction with enzyme catalysis at therapeutic concentrations. This may have clinical implications for HIV treatment in children and adults. However, so far, clinical data are scarce, and further studies are needed to be able to draw clinical conclusions.
Identifiants
pubmed: 31256164
pii: 000500522
doi: 10.1159/000500522
doi:
Substances chimiques
Alkynes
0
Benzoxazines
0
Cyclopropanes
0
Reverse Transcriptase Inhibitors
0
CYP21A2 protein, human
EC 1.14.14.16
Steroid 21-Hydroxylase
EC 1.14.14.16
efavirenz
JE6H2O27P8
Types de publication
Case Reports
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
262-270Informations de copyright
© 2019 S. Karger AG, Basel.