HIV Drug Efavirenz Inhibits CYP21A2 Activity with Possible Clinical Implications

Abstract

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: 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: 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: 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: 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.

The effects of selected inhibitors on human fetal adrenal steroidogenesis differs under basal and ACTH-stimulated conditions

“…The inhibitors were chosen based on their reported steroidogenic enzyme target in the classic adrenal steroidogenic pathway. Hence, Abiraterone acetate inhibits 17α-hydroxylase and 17,20-lyase activities of CYP17A1, Osilodrostat inhibits the 11βhydroxylase activity of CYP11B1/2 and the aldosterone synthase activity of CYP11B2, while Efavirenz has been suggested to inhibit CYP21A2 [9] (Fig. 1c).…”

“…Treatment of imbalanced steroid hormone levels depends on the cause of the disease but can involve hormone replacement therapy and medication targeting excess steroid hormone production. In addition to the therapies used to specifically target adrenal disorders, therapeutic drugs used for other indications can have undesired side-effects on adrenal function, including Efavirenz which is used for treatment of HIV but has been suspected to also inhibit adrenal steroidogenesis [9].…”

“…However, our recently established HFA ex vivo culture model provides a model to examine de novo steroid hormone production and manipulated steroidogenic activity under basal and ACTH-stimulated conditions [17]. Thus, this study aimed to examine the effects of the CYP17A1 inhibitor Abiraterone acetate, the CYP11B1/2 inhibitor Osilodrostat, and the proposed CYP21A2 inhibitor Efavirenz [9] on HFA tissue cultured ex vivo. Changes in classic adrenal steroid secretion following inhibitor treatment were investigated under basal and ACTH-stimulated conditions, and effects on HFA tissue expression of steroidogenic enzymes were examined.…”

Integrated bioinformatics analysis for the screening of hub genes and therapeutic drugs in severe acute respiratory syndrome corona virus 2 infection/COVID 19

“…Enriched genes such as IL6 [104] and JAK2 [105] were responsible for progression of SARS-CoV-2 infection. Enriched genes such as TICAM1 [106], OAS1 [107], OAS2 [108], CXCL9 [109], EREG (epiregulin) [110], CCL22 [111], VCAM1 [112], IFI35 [113], IFIT2 [114], TRIM5 [115], XAF1 [116], IFI6 [117], IL7 [118], SP100 [119], GBP1 [120], GBP2 [121], IRF4 [122], MIR5193 [123], IFNL3 [124], CYP21A2 [125], CXCL5 [126], CX3CL1 [127], CCL4L1 [128], WNT16 [129], GNB3 [130], FLG ( laggrin) [131] and HEY1 [132] were responsible for progression of various viral infections, but these genes may be involved in the development of SARS-CoV-2 infection. Expression of NOS2 was associated with development of rhinovirus infection [133], but this gene may be involved in progression of SARS-CoV-2 infection.…”

Differential effects of variations in human P450 oxidoreductase on the aromatase activity of CYP19A1 polymorphisms R264C and R264H

“…Two different types of the cytochrome P450 family of proteins are present in humans [5]. The P450 type 1 proteins are found in the mitochondrion and are responsible for the metabolism of steroid hormones and sterols and are targets for drugs in a range of disorders [6][7][8][9][10][11]. The P450 type 2 proteins are localized in the endoplasmic reticulum and have a range of metabolic activities, including drugs, xenobiotics as well as endogenous substrates, and steroid hormones like progesterone, dehydroepiandrosterone, and testosterone [12][13][14][15][16][17].…”