2009 - INHIBITION OF HUMAN STEROID 5B-REDUCTASE (AKR1D1) BY FINASTERIDE AND STRUCTURE OF THE ENZYME-INHIBITOR COMPLEX
Note the consequences that Finasteride usage might prevent its own metabolism.
"… The Δ4-3-ketosteroid functionality is present in many important steroid hormones, e.g., testosterone, cortisone, and progesterone. An initial step in steroid hormone metabolism is the reduction of the Δ4-ene, which in humans is mediated by steroid 5α-reductases (SRD5A1,
SRD5A2) or steroid 5β-reductase (AKR1D1) to yield the corresponding 5α- or 5β-dihydrosteroids, respectively (1,2).
The products of these reactions are not always inactive. 5α-Reductase is responsible for the conversion of testosterone to 5α-dihydrotestosterone, which is the most potent natural ligand for the androgen receptor. By contrast, in addition to being involved in bile-acid biosynthesis, [b]5β-reductase is responsible for generating 5β-pregnanes which are natural ligands for the pregnane-X receptor (PXR) in the liver /b. [b]PXR is involved in the induction of CYP3A4, which is responsible for the metabolism of a large proportion of drugs /b. Thus both 5α- and 5β-reductase are involved in the formation of potent ligands for nuclear receptors.
…“Finasteride was originally thought to act as a competitive inhibitor with nanomolar affinity for 5α-reductase type 2 (12). More recently, it was found that finasteride acts as a mechanism-based inactivator of this enzyme (13).”
…“AKR1D1 [5β-reductase] is inhibited by the 5α-reductase type 2 selective inhibitor finasteride, by acting solely as a reversible competitive inhibitor.”
Both AKR1D1 [5β-reductase] and 5α-reductase type 1 play important roles in the hepatic clearance of steroid hormones, suggesting that high-dose finasteride may have an adverse effect on hepatic steroid metabolism.
Inhibition of AKR1D1 [5β-reductase] by high-dose finasteride would also deprive PXR of its natural 5β-pregnane ligands, resulting in diminished CYP3A4 induction. This could result in significant drug-drug interactions.
Importantly, finasteride itself is metabolized by CYP3A4, suggesting that high-dose finasteride might prevent its own metabolism (27)."
INHIBITION OF HUMAN STEROID 5B-REDUCTASE (AKR1D1) BY FINASTERIDE AND STRUCTURE OF THE ENZYME-INHIBITOR COMPLEX.pdf (1.29 MB)