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- W2945251889 abstract "5209 Human aldo-keto reductases (AKR1C1-AKR1C4 and AKR1A1) have been shown to oxidize polycyclic aromatic (PAH) trans-dihydrodiols to reactive and redox-active o-quinones in vitro, in transformed human bronchoalveolar cells, and in A549 adenocarcinoma cell lysates which overexpress these isoforms. Recently, AKR1B10 (aldose reductase-like protein) was shown to be highly expressed in non-small cell lung carcinoma (Fukumoto et al., Clin. Cancer Res. (2005) 11, 1776-1785), raising the possibility that this enzyme may also activate PAH trans-dihydrodiols. We now report that members of the aldo-keto reductase AKR1B subfamily have dihydrodiol dehydrogenase activity in vitro. Homogenous recombinant AKR1B10 was expressed as a His-tag fusion protein and had identical steady-state kinetic constants to those previously assigned for DL-glyceraldehyde. This enzyme was found to oxidize benzo[a]pyrene(BP)-trans-7,8-dihydrodiol to BP-7,8-dione but with the incorrect stereochemistry to be relevant for BP activation in vivo. However, AKR1B10 can activate both stereoisomers of benzo[g]chrysene-11,12-diol (fjord-region) and 7,12-dimethylbenz[a]anthracene-3,4-diol (methylated bay region), with v/[S] values comparable to those observed for BP-7,8-diol oxidation by human AKR1C enzymes. These studies were extended to include the highly homologous protein AKR1B1 (aldose reductase, 71% amino acid identity). Homogenous recombinant protein was also found to oxidize PAH trans-dihydrodiols, including BP-7,8-diol. These studies implicate a novel role for AKR1B enzymes in PAH activation and hence tobacco smoke carcinogenesis. (Supported by PO1 CA092537 and R01 CA39504 awarded to T.M.P. and R25 CA101871 awarded to A.M.Q.)" @default.
- W2945251889 created "2019-05-29" @default.
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- W2945251889 date "2006-04-15" @default.
- W2945251889 modified "2023-09-23" @default.
- W2945251889 title "Oxidation of PAH trans-dihydrodiols by human aldo-keto reductase (AKR) 1B isoforms: A new AKR subfamily implicated in PAH activation." @default.
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