CBR1 and CBR3 pharmacogenetics and their influence on doxorubicin disposition in Asian breast cancer patients

Abstract

The present study aimed to identify polymorphic genes encoding carbonyl reductases (CBR1, CBR3) and investigate their influence on doxorubicin disposition in Asian breast cancer patients (n = 62). Doxorubicin (60 mg/m 2 ) was administered every 3 weeks for four to six cycles and the pharmacokinetic parameters were estimated using non-compartmental analysis (WinNonlin). The Mann-Whitney U-test was used to assess genotypic-phenotypic correlations. (1) The phase I and II enzymes are expressed abundantly in hepatic tissues and display large interindividual variations in their metabolic capacities toward a wide array of therapeutic agents.The CBR are ubiquitously expressed monomeric NADPHdependent cytosolic enzymes that catalyze the reduction of chemically diverse substrates such as aldehydes, ketones, quinones, and other xenobiotics.(2,3) Apart from the metabolism of endogenous compounds and drug detoxification, CBR are also assumed to participate in cellular processes such as signal transduction, (4) apoptosis,mutagenesis,carcinogenesis,and drug resistance.(8) Four CBR isoforms (CBR1, CBR2, CBR3, and CBR4) that were initially assigned to the aldo-keto reductase (AKR) family are now classified under the family of short-chain dehydrogenases and represent one of the largest protein families identified to date.(9) CBR1 is the major carbonyl reductase and is expressed widely in different tissues. The CBR1 gene is mapped to chromosome 21q22.12, has three exons spanning 3.3 kb, and encodes a 30-kDa monomeric protein comprising 277 amino acids. The CBR1 gene lacks a CAAT and TATA box and contains a GC-rich island extending into the first exon, a structure characteristic of genes having a housekeeping function.(4) The identified substrates of human CBR1 include endogenous compounds (prostaglandins and steroids) and drugs such as loxoprofen, (4) metyrapone, (10) haloperidol, (11) bromoperidol,timirepone, (13) and doxorubicin. (14) CBR2 has low sequence identity with CBR1 and has not been identified in human tissues. The CBR3 gene contains three exons spanning a region of 11.2 kb and has a 72% sequence similarity with CBR1. It is located 62 kb telomeric to the CBR1 gene. Although widely expressed, the relative expression of CBR3 is much lower than CBR1 in most of the tissues analyzed.(15) The CBR4 gene is located on human chromosome 4 (4q32.3) and encodes a protein composed of 237 amino acids, but its enzymatic properties and tissue distribution remain unknown. (15) To date, there are limited studies investigating the influence of genetic polymorphisms in the CBR genes on the pharmacokinetics and pharmacodynamics of drugs. Avramopoulos et al. identified the CBR1 3′-untranslated region (UTR) G>A transition for the linkage mapping of the CBR gene on chromosome 21. (16) However, the effect of the polymorphism on enzyme activity and tissue expression is not known. Gonzalez-Covarrubias et al. reported the V88I (262G>A, rs1143663), L73L (312G>C, rs25678), A209A (720C>T, rs20572), and V231V (786G>A, rs2230192) polymorphisms by scree...

Pharmacokinetic and pharmacodynamic study on amrubicin and amrubicinol in Japanese patients with lung cancer

“…Genetic polymorphisms of these metabolic enzymes are reportedly related to the PK of several anticancer agents [16][17][18]. CBR-1 D2 diplotypes tagged by at least one variant allele at the CBR-1 c.627C [ T and ?967G [ A loci are correlated with significantly higher exposure levels of doxorubicin, suggesting the possibility that the intracellular conversion to doxorubicinol is reduced in Asian patients with breast cancer [15].…”

<b><i>NOS3</i></b> 895G&gt;T and <b><i>CBR3</i></b> 730G&gt;A Are Associated with Recurrence Risk in Non-Muscle-Invasive Bladder Cancer with Intravesical Instillations of THP

“…The transcriptional regulation of the CBR3 gene may affect the physiologic role of CBR3, since molecular mechanisms that regulate an enzyme's expression are often closely related to its function. CBR1 1096G>A (rs9024) and CBR3 730G>A (rs1056892) were tested for their probable association with the efficacy of doxorubicin chemotherapy efficacy in previous studies of breast cancer patients [19]. Fan et al [20] (2008) reported that polymorphisms in CBR3 may explain the interindividual and interethnic variability of doxorubicin pharmacokinetics and pharmacodynamics.…”

Human Carbonyl Reductases

“…The interindividual differences in carbonyl reductase activity may in part reflect variable rates of CBR1 gene transcription which was revealed to be regulated by the aryl hydrocarbon receptor (AhR) pathway [46,47]. Further, CBR1 polymorphism is suspected to play a role in variable CBR1 activity and expression since CBR1 polymorphisms were detected to be associated with various CBR1 expression levels or isoforms with distinct enzymatic properties [44,48,49].…”