The modulation of carbonyl reductase 1 by polyphenols

Abstract

Carbonyl reductase 1 (CBR1), an enzyme belonging to the short-chain dehydrogenases/reductases family, has been detected in all human tissues. CBR1 catalyzes the reduction of many xenobiotics, including important drugs (e.g. anthracyclines, nabumetone, bupropion, dolasetron) and harmful carbonyls and quinones. Moreover, it participates in the metabolism of a number of endogenous compounds and it may play a role in certain pathologies. Plant polyphenols are not only present in many human food sources, but are also a component of many popular dietary supplements and herbal medicines. Many studies reviewed herein have demonstrated the potency of certain flavonoids, stilbenes and curcuminoids in the inhibition of the activity of CBR1. Interactions of these polyphenols with transcriptional factors, which regulate CBR1 expression, have also been reported in several studies. As CBR1 plays an important role in drug metabolism as well as in the protection of the organism against potentially harmful carbonyls, the modulation of its expression/activity may have significant pharmacological and/or toxicological consequences. Some polyphenols (e.g. luteolin, apigenin and curcumin) have been shown to be very potent CBR1 inhibitors. The inhibition of CBR1 seems useful regarding the increased efficacy of anthracycline therapy, but it may cause the worse detoxification of reactive carbonyls. Nevertheless, all known information about the interactions of polyphenols with CBR1 have only been based on the results of in vitro studies. With respect to the high importance of CBR1 and the frequent consumption of polyphenols, in vivo studies would be very helpful for the evaluation of risks/benefits of polyphenol interactions with CBR1.

Kinetic features of carbonyl reductase 1 acting on glutathionylated aldehydes

“…Results are reported in Table 1; the resulting inhibitory pattern appeared similar, but not identical, to what previously observed using isatin as substrate of CBR1 [24]. Rutin appeared to be the most potent of the compounds tested.…”

“…reported to affect CBR1 activity, depending on their structural features and also on the substrate used to detect the activity [23,24]. Thus, it could be important to evaluate the effect of inhibitors on the hCBR1 catalyzed GSHNE transformation.…”

“…Moreover, as recently reported [44], CBR1 positively affects neuronal cell survival and confers protection against oxidative stress-induced brain degeneration. For all these, as highlighted by Bousova et al [24], the potential of polyphenols (or other naturally occurring molecules) to interfere with CBR1 activity may lead to an alteration of cell homeostasis. These considerations, together with the observed pro-oxidant action of polyphenols [45], suggest a balanced dietary intake of these molecules for healthy subjects.…”

Carbonyl reductase 1 catalyzes 20β-reduction of glucocorticoids, modulating receptor activation and metabolic complications of obesity

“…These findings are important since there are wide variations in CBR1 activity between individuals, in disease and after consumption of a number of naturally occurring CBR1 inhibitors: human tissue CBR1 expression and activity varies significantly between ethnic groups 6 ; CBR1 expression and activity is increased in Down’s syndrome due to the location of the CBR1 gene on chromosome 21 48 ; CBR1 inhibitors such as flavonoids and polyphenols are present in many foods and supplements 49 and reported enhancers of CBR1 activity include components of cigarette smoke 7 . Our data suggest the resulting variation of CBR1/20β-DHF has important consequences for glucocorticoid metabolism and GR activation in health and disease.…”

Nerolidol and Farnesol Inhibit Some Cytochrome P450 Activities but Did Not Affect Other Xenobiotic-Metabolizing Enzymes in Rat and Human Hepatic Subcellular Fractions

“…Distinct enzymes, belonging to several families, mainly to aldo-keto reductases (AKR) and short-chain dehydrogenases/reductases, reduce carbonyl groups. These reductases often show broad and overlapping substrate specificities and some well-characterized members (e.g., CBR1, AKR1A, AKR1C, or NQO1), and have protective roles toward xenobiotic carbonyls and quinones, because metabolic reduction leads to less toxic products, which can be further conjugated with endogenous substrate and excreted [ 15 , 16 , 17 , 18 ].…”