Pharmacogenetics of human carbonyl reductase 1 (CBR1)in livers from black and white donors

Abstract

Carbonyl reductase 1 (CBR1) reduces the anticancer drug doxorubicin into the cardiotoxic metabolite doxorubicinol. We documented the hepatic expression of CBR1 in samples from white and black donors. Concordance between ethnicity and geographical ancestry was examined with ancestry informative markers. Livers from blacks and whites showed similar CBR1 mRNA levels (CBR1 mRNA blacks = 4.8 ± 4.3 relative -fold versus CBR1 mRNA whites =3.6 ± 3.6 relative -fold; p = 0.217). CBR1 protein levels did not differ between both groups (CBR1 blacks = 8.0 ± 3.4 nmol/g cytosolic protein versus CBR1 whites = 9.0 ± 4.6 nmol/g cytosolic protein; p =0.347). The CBR1 3′-untranslated region polymorphism 1096G> A was detected in DNA samples from whites (p = 0.875; q = 0.125), and livers with homozygous G/G genotypes showed a trend toward higher CBR1 mRNA levels compared with samples with heterozygous G/A genotypes [CBR1 1096G>A (G/G) = 4.1 ± 4.1 relative -fold versus CBR1 1096G>A (G/A) = 3.0 ± 2.5 relative -fold; p = 0.266]. CBR1 1096G>A genotype status was associated with CBR1 protein levels (p = 0.030) and CBR activity expressed as the rate of synthesis of doxorubicinol (p = 0.028). Our findings warrant further studies to evaluate the impact of CBR1 1096G> A genotype status on the variable pharmacodynamics of anthracycline drugs. Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics.