Skip Navigation

Publication Detail

Title: Individual variability in the detoxification of carcinogenic arylhydroxylamines in human breast.

Authors: Rhoads, Keelia; Sacco, James C; Drescher, Nicholas; Wong, Amos; Trepanier, Lauren A

Published In Toxicol Sci, (2011 Jun)

Abstract: Cytochrome b(5) (b5) and NADH cytochrome b(5) reductase (b5R) detoxify reactive hydroxylamine (NHOH) metabolites of known arylamine and heterocyclic amine mammary carcinogens. The aim of this study was to determine whether NHOH reduction for the prototypic arylamine 4-aminobiphenyl (4-ABP) was present in human breast and to determine whether variability in activity was associated with single nucleotide polymorphisms (SNPs) in the coding, promoter, and 3'untranslated region (UTR) regions of the genes encoding b5 (CYB5A) and b5R (CYB5R3). 4-ABP-NHOH reduction was readily detected in pooled human breast microsomes, with a K(m) (280ýýM) similar to that found with recombinant b5 and b5R, and a V(max) of 1.12 ýý 0.19 nmol/min/mg protein 4-ABP-NHOH reduction varied 75-fold across 70 individual breast samples and correlated significantly with both b5 (80-fold variability) and b5R (14-fold) immunoreactive protein. In addition, wide variability in b5 protein expression was significantly associated with variability in CYB5A transcript levels, with a trend toward the same association between b5R and CYB5R3. Although a sample with a novel coding SNP in CYB5A, His22Arg, was found with low reduction and b5 expression, no other SNPs in either gene were associated with outlier activity or protein expression. We conclude that b5 and b5R catalyze the reduction of 4-ABP-NHOH in breast tissue, with very low activity, protein, and messenger RNA expression in some samples, which cannot be attributed to promoter, coding, or 3'UTR SNPs. Further studies are underway to characterize the transcriptional regulation of CYB5A and CYB5R3 and begin to understand the mechanisms of individual variability in this detoxification pathway.

PubMed ID: 21447608 Exiting the NIEHS site

MeSH Terms: 3' Untranslated Regions; Adolescent; Adult; African Americans; Aged; Aged, 80 and over; Breast Neoplasms/genetics; Breast Neoplasms/metabolism; Breast/metabolism*; Carcinogens/toxicity*; Cytochrome-B(5) Reductase/genetics; Cytochrome-B(5) Reductase/metabolism; Cytochromes b5/genetics; Cytochromes b5/metabolism; European Continental Ancestry Group; Female; Gene Expression Regulation; Humans; Hydroxylamine/toxicity*; Kinetics; Metabolic Detoxication, Drug*; Microsomes/metabolism; Middle Aged; Polymorphism, Single Nucleotide; RNA, Messenger; Sequence Analysis, DNA; Young Adult

Back
to Top