CBR1

Function

Carbonyl reductase is one of several monomeric, NADPH-dependent oxidoreductases having wide specificity for carbonyl compounds. This enzyme is widely distributed in human tissues. Another carbonyl reductase gene, CBR3, lies close to this gene on chromosome 21q22.12. CBR1 metabolizes many toxic environmental quinones and pharmacological relevant substrates such as the anticancer doxorubicin. Several studies have shown that CBR1 plays a protective role in oxidative stress, neurodegeneration, and apoptosis. In addition, CBR1 inactivates lipid aldehydes during oxidative stress in cells. Therefore, CBR1 may play a beneficial role in protecting against cellular damage resulting from oxidative stress.

Polymorphisms

Up-to-date two non-synonymous polymorphisms on CBR1 have been identified. The CBR1 V88I polymorphism encodes for a valine-to-isoleucine substitution at position 88 of the aminoacid chain. In vitro studies with recombinant proteins indicate that the CBR1 V88 isoform has a higher Vmax towards the substrates menadione (vitamin K3) and daunorubicin. Recent studies in human liver cytosols show that an untranslated polymorphism on the 3'UTR region of the CBR1 gene (rs9024) is associated with higher levels of the cardiotoxic metabolite doxorubicinol.

Structure

Gene

Human CBR1 gene includes 8 exons.

Protein

The enzyme consists of 277 amino acid residues and is widely distributed in human tissues such as liver, epidermis, stomach, small intestine, kidney, neuronal cells, and smooth muscle fibers. The best substrates of CBR1 are quinones, including ubiquinone-1 and tocopherolquinone (vitamin E). Ubiquinones (coenzyme Q) are constitutive parts of the respiratory chain, and tocopherolquinone protects lipids of biological membranes against lipid peroxidation, indicating that CBR1 may play an important role as an oxidation–reduction catalyst in biological processes.

Clinical significance

CBR1 has been reported to relate to tumor progression. Suppression of CBR1 expression was associated with poor prognosis in uterine endometrial cancer and uterine cervical squamous cell carcinoma. Previous studies showed that decreased CBR1 expression is associated with lymph node metastasis and poor prognosis in ovarian cancer, and induction of CBR1 expression in ovarian tumors leads to a spontaneous decrease in tumor size.

Recent study demonstrates that CBR1 attenuates apoptosis and promotes cell survival in pancreatic β cell lines under glucotoxic and glucolipotoxic conditions via reducing ROS generation. Their data demonstrates that CBR1 expression level and enzyme activity are decreased in pancreatic islets isolated from db/db mice, an animal model of type 2 diabetes. These results suggest that CBR1 may play a role in protecting pancreatic β-cells against oxidative stress under glucotoxic or glucolipotoxic conditions, and its reduced expression or activity may contribute to β-cell dysfunction in db/db mice or human type 2 diabetes.

In addition, CBR1 may play a critical role in prostaglandin F2α (PGF2α) synthesis in human amnion fibroblasts, and cortisol promotes the conversion of PGE2 into PGF2α via glucocorticoid receptor (GR)-mediated induction of CBR1 in human amnion fibroblasts. This stimulatory effect of cortisol on CBR1 expression may partly explain the concurrent increases of cortisol and PGF2α in human amnion tissue with labor, and these findings may account for the increased production of PGF2α in the fetal membranes prior to the onset of labor.

Interactions

CBR1 has been shown to interact with Cortisol, C2 domain, and Flavonoid.

References

References

1. "Entrez Gene: CBR1 carbonyl reductase 1".
2. (Jan 1993). "Human carbonyl reductase (CBR) localized to band 21q22.1 by high-resolution fluorescence in situ hybridization displays gene dosage effects in trisomy 21 cells". Genomics.
3. (Mar 2009). "The SDR (short-chain dehydrogenase/reductase and related enzymes) nomenclature initiative". Chemico-Biological Interactions.
4. (Apr 1986). "Carbonyl reductase provides the enzymatic basis of quinone detoxication in man". Biochemical Pharmacology.
5. (Mar 2000). "Carbonyl reductase: a novel metastasis-modulating function". Cancer Research.
6. (Feb 2006). "Neuroprotective role for carbonyl reductase?". Biochemical and Biophysical Research Communications.
7. (Jun 2007). "A functional genetic polymorphism on human carbonyl reductase 1 (CBR1 V88I) impacts on catalytic activity and NADPH binding affinity". Drug Metabolism and Disposition.
8. "Reference SNP Cluster Report: rs9024". National Center for Biotechnology Information/National Institutes of Health.
9. (Feb 2009). "Pharmacogenetics of human carbonyl reductase 1 (CBR1) in livers from black and white donors". Drug Metabolism and Disposition.
10. (Nov 2010). "Carbonyl reductase 1 protects pancreatic β-cells against oxidative stress-induced apoptosis in glucotoxicity and glucolipotoxicity". Free Radical Biology & Medicine.
11. (Feb 1981). "Purification and properties of an NADPH-dependent carbonyl reductase from human brain. Relationship to prostaglandin 9-ketoreductase and xenobiotic ketone reductase". The Journal of Biological Chemistry.
12. (1 October 2012). "Decreased carbonyl reductase 1 expression promotes malignant behaviours by induction of epithelial mesenchymal transition and its clinical significance.". Cancer Letters.
13. (March 2015). "Decreased expression of carbonyl reductase 1 promotes ovarian cancer growth and proliferation.". International Journal of Oncology.
14. (August 2014). "Induction of PGF2α synthesis by cortisol through GR dependent induction of CBR1 in human amnion fibroblasts.". Endocrinology.
15. (16 October 2015). "Structural Basis for Ca2+-mediated Interaction of the Perforin C2 Domain with Lipid Membranes.". The Journal of Biological Chemistry.
16. (April 1971). "A follow-up study of wrist slashers.". The American Journal of Psychiatry.