@article{ref1,
title="Suicidal inactivation of human dihydropyrimidine dehydrogenase by (E)-5-(2-bromovinyl)uracil derived from the antiviral, sorivudine",
journal="Cancer Letters",
year="1998",
author="Ogura, K. and Nishiyama, T. and Takubo, H. and Kato, A. and Okuda, H. and Arakawa, K. and Fukushima, M. and Nagayama, S. and Kawaguchi, Y. and Watabe, T.",
volume="122",
number="1-2",
pages="107-113",
abstract="An enzymatic study was performed to clarify the mechanism of 18 acute deaths in patients who had received the new oral antiviral drug, sorivudine (SRV), during anticancer chemotherapy with 5-fluorouracil (5-FU) prodrugs. Human dihydropyrimidine dehydrogenase (hDPD), playing a key role in the liver as the rate-limiting enzyme in catabolism of 5-FU, was expressed in E. coli, purified and incubated in the presence of NADPH with SRV or (E)-5-(2-bromovinyl)uracil (BVU), a metabolite of SRV produced by human gut flora. hDPD was rapidly and irreversibly inactivated by BVU, but not by SRV. Radioactivity of [14C]BVU was incorporated into hDPD in the presence of NADPH in a manner reciprocal to the enzyme inactivation. In the absence of NADPH, hDPD was not inactivated by BVU, nor radiolabeled with [14C]BVU. Thus, as we demonstrated previously with studies using the rat, the acute deaths were strongly suggested to be attributable to markedly elevated tissue 5-FU levels which were responsible for irreversible inhibition of hDPD by covalent binding of a reduced form of BVU as a suicide inactivator.<p /><p>Language: en</p>",
language="en",
issn="0304-3835",
doi="10.1016/s0304-3835(97)00377-7",
url="http://dx.doi.org/10.1016/s0304-3835(97)00377-7"
}