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Extraadrenal 21-hydroxylation by CYP2C19 and CYP3A4: effect on 21-hydroxylase deficiency
Larissa G Gomes1, Ningwu Huang, Vishal Agrawal
1Department of Pediatrics, HSE-1401, 513 Parnassus Avenue, University of California, San Francisco, San Francisco, California 94143-0978, USA.
The Journal of Clinical Endocrinology and Metabolism
|October 30, 2008
Summary
Hepatic enzymes CYP2C19 and CYP3A4 can 21-hydroxylate progesterone, potentially mitigating mineralocorticoid deficiency in 21-hydroxylase deficiency (21OHD). However, they do not impact glucocorticoid deficiency, suggesting other enzymes contribute to extra-adrenal 21-hydroxylation.
Area of Science:
- Biochemistry
- Genetics
- Endocrinology
Background:
- 21-Hydroxylase deficiency (21OHD) results from CYP21A2 gene mutations, impacting adrenal 21-hydroxylase (P450c21) function.
- While CYP21A2 mutations correlate with 21OHD phenotype, some patients exhibit residual activity, suggesting alternative 21-hydroxylation pathways.
- The role of hepatic P450 enzymes in modifying 21OHD phenotypes is not well understood.
Purpose of the Study:
- To investigate the 21-hydroxylation capacity of hepatic CYP2C19 and CYP3A4 for progesterone and 17-hydroxyprogesterone (17OHP).
- To assess the influence of the P450 oxidoreductase (POR) A503V variant on these enzymatic activities.
- To explore the correlation between CYP2C19 variants and clinical phenotypes in patients with 21OHD.
Main Methods:
- Recombinant human P450c21, CYP2C19, and CYP3A4 were expressed and combined with wild-type and A503V POR.
- The 21-hydroxylation of radiolabeled progesterone and 17OHP was quantified, measuring kinetic parameters (Km and Vmax).
- CYP2C19 genotyping was performed on 21OHD patients with genotypes predicting severe congenital adrenal hyperplasia.
Main Results:
- CYP2C19 and CYP3A4 exhibited significantly lower Vmax/Km ratios for progesterone 21-hydroxylation compared to P450c21 (17% and 10%, respectively).
- CYP2C19 and CYP3A4 showed higher Km values for progesterone 21-hydroxylation than P450c21, indicating lower substrate affinity.
- Neither CYP2C19 nor CYP3A4 could 21-hydroxylate 17OHP; the CYP2C19*17 allele was found in a patient with a milder 21OHD phenotype than predicted.
Conclusions:
- CYP2C19 and CYP3A4 possess the ability to 21-hydroxylate progesterone, potentially ameliorating mineralocorticoid deficiency in 21OHD.
- These enzymes do not significantly impact glucocorticoid deficiency, as they do not hydroxylate 17OHP.
- The findings suggest that multiple enzymes likely contribute to extra-adrenal 21-hydroxylation, influencing the overall 21OHD phenotype.
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