AKR1C4

AKR1C4 Full Name

aldo-keto reductase family 1, member C4

AKR1C4 Introduction

Aldo-keto reductase family 1 member C4 (AKR1C4), also known as 3α-hydroxysteroid dehydrogenase type 1 (3α-HSD1) or chlordecone reductase, is a member of the aldo-keto reductase (AKR) superfamily of NAD(P)H-dependent oxidoreductases. Encoded by the AKR1C4 gene on chromosome 10p15.1 within the AKR1C gene cluster (alongside AKR1C1, AKR1C2, and AKR1C3), AKR1C4 is predominantly expressed in the liver and functions primarily in steroid hormone metabolism, particularly in bile acid biosynthesis and the clearance of steroid hormones. The enzyme catalyzes the NADPH-dependent reduction of various carbonyl-containing substrates including 3-ketosteroids, prostaglandins, and xenobiotic carbonyl compounds.

Figure 1. Strcuture of AKR1C4.

Bile Acid Biosynthesis and Steroid Metabolism
AKR1C4 plays a critical role in hepatic bile acid biosynthesis by catalyzing the stereospecific reduction of key 3-keto intermediates in the classical and alternative bile acid synthetic pathways. Specifically, AKR1C4 converts 7α-hydroxy-4-cholesten-3-one and 7α,12α-dihydroxy-4-cholesten-3-one to their corresponding 3α-hydroxylated products, essential steps in the synthesis of chenodeoxycholic acid and cholic acid, the primary bile acids in humans. The enzyme exhibits high substrate specificity for steroid substrates with a 5β-hydrogen configuration. Additionally, AKR1C4 participates in the hepatic inactivation of androgens by reducing 5α-dihydrotestosterone (DHT) to 5α-androstane-3α,17β-diol and androsterone, contributing to the regulation of circulating androgen levels. Its expression is regulated by the farnesoid X receptor (FXR) and liver X receptor (LXR), integrating bile acid homeostasis with lipid metabolism.

Pharmacogenetics, Drug Metabolism, and Disease Associations
AKR1C4 exhibits significant inter-individual variation in expression and activity due to genetic polymorphisms in the AKR1C4 gene, with implications for bile acid metabolism and drug disposition. Non-synonymous single nucleotide polymorphisms (SNPs) resulting in amino acid substitutions (e.g., Leu311Val) have been identified that alter enzyme kinetics and substrate specificity. AKR1C4 also metabolizes certain xenobiotic compounds, including the pesticide chlordecone (hence the alternative name), and participates in the metabolic activation or detoxification of carbonyl-containing drugs. Polymorphisms in the AKR1C gene cluster have been associated with altered risk for hormone-dependent cancers, including prostate cancer and breast cancer, potentially through modulation of steroid hormone metabolism. Furthermore, dysregulation of AKR1C4 expression has been observed in non-alcoholic fatty liver disease (NAFLD) and cholestatic liver disorders, implicating altered bile acid metabolism in these conditions.

Alternate Names for AKR1C4

AKR1C4; aldo-keto reductase family 1, member C4; C11; CDR; DD4; CHDR; DD-4; HAKRA; 3-alpha-HSD; aldo-keto reductase family 1 member C4