Measurement and characterization of the denitrosation of tauromustine and related nitrosoureas by glutathione transferases in liver cytosol from various species.

Abstract:

:The denitrosation of a novel nitrosourea, 1-(2-chloroethyl)-3-[(2-dimethylaminosulfonyl)-ethyl]-1-nitrosoure a, tauromustine (TCNU), has been investigated in liver cytosol from various species and with a pool of cytosolic rat liver glutathione transferases (GSTs). In addition, the denitrosation of related nitrosoureas, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) have been investigated. By using radioactive nitrosoureas as substrates and HPLC to detect the denitrosated products, a sensitive assay has been developed. The activities towards additional substrates, 1-chloro-2,4-dinitrobenzene (CDNB) and trans-stilbene oxide (tSBO) were also measured in the various cytosol fractions. The apparent Vmax and Km values for the denitrosation of TCNU in rat liver cytosol were calculated to be 830 pmol/min/mg protein and 8.4 mM respectively. The rate of denitrosation of TCNU was found to be highest in the mouse, followed by the rat and the dog. The induction of GSTs by phenobarbital in rats increased the denitrosation of TCNU similar to the activities found towards CDNB and tSBO as substrates. The highest denitrosation activity by GST was determined towards BCNU, followed by CCNU and TCNU. Our results suggest that the denitrosation of various nitrosoureas via GST may play an important role in the deactivating process occurring in vivo and for the efficacy of nitrosoureas used in chemotherapy.

journal_name

Carcinogenesis

journal_title

Carcinogenesis

authors

Tuvesson H,Gunnarsson PO,Seidegård J

doi

10.1093/carcin/14.6.1143

subject

Has Abstract

pub_date

1993-06-01 00:00:00

pages

1143-7

issue

6

eissn

0143-3334

issn

1460-2180

journal_volume

14

pub_type

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