Biological functions and biosynthesis of Corticosteroids
Structure and biosynthesis
Structural features and biosynthetic pathways
All vertebrate steroid hormones including corticosteroids are synthesized from cholesterol by steroidogenic enzymes located in the endoplasmic reticulum and mitochondria. Corticosteroids are synthesized in the adrenal cortex in the kidney.
The steroidogenic enzymes, 3β-hydroxysteroid dehydrogenase (3β-HSD) and five different cytochrome P450s (CYP11A1, CYP17, CYP21, CYP11B1, and CYP11B2), are necessary for corticosteroid production from cholesterol. CYP11A1 is a side chain cleavage enzyme, CYP17is a steroid 17α-hydroxylase and 17,20-lyase, CYP21 is a steroid 21-hydroxylase, CYP11B1 is a steroid 11β-hydroxylase, and CYP11B2 is an aldosterone synthase.
Cholesterol is converted to pregnenolone by cytochrome CYP11A1 in mitochondria, and then pregnenolone is converted to 11-deoxycortisol, 11-deoxycorticosterone, and dehydroepiandrosterone (DHEA) or androstenedione by enzymes in the endoplasmic reticulum. 11-Deoxycortisol and 11-deoxycorticosterone migrate to the mitochondria, where they are converted to cortisol and corticosterone, respectively, by CYP11B.2,4 Further, corticosterone is converted to aldosterone by CYP11B1 or CYP11B2 localized in the mitochondria.2–4 Corticosteroid production in the adrenal cortex is regulated by the pituitary hormone adrenocorticotropin (ACTH) ,which is released from the pituitary gland, and ACTH production is regulated by the hypothalamic corticotropin-releasing hormone (CRH). Aldosterone secretion is promoted by angiotensin II, and potassium ion with ACTH in the blood.
Biological functions
Target cells/tissues and functions
Corticosteroids are important regulators of the stress response, carbohydrate metabolism, protein catabolism, sodium retention in the kidney, and inflammation regulation. Corticosteroids also are involved in bone development, blood electrolyte levels, and behavior.MR and GR are widely distributed in the body. Although the traditional function of the MR is to regulate electrolyte transport in the kidney, the MR has other functions in the brain, heart, and adipose tissue.
Phenotype of gene-modified animals Homozygous MR-deficient mice have normal prenatal development, and during the first week of life, these animals develop symptoms of pseudohypoaldosteronism,lose weight, and eventually die at around day 10 due to kidney failure. GR null mice die within hours after birth because of respiratory failure. They have atelectatic lungs, impaired liver function, an impaired hypothalamuspituitary-adrenal (HPA) axis, increased plasma levels of ACTH and corticosterone, and enlarged adrenal glands that produce no adrenaline.
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