Wp. Frankmoelle et al., Glutathione S-transferase metabolism of the antineoplastic pentafluorophenylsulfonamide in tissue culture and mice, DRUG META D, 28(8), 2000, pp. 951-958
The microtubule disrupting agent 2-fluoro-1-methoxy-4-pentafluorophenylsulf
onamidobenzene (T138067) binds covalently and selectively to beta-tubulin a
nd has been shown to evade drug-efflux pumps that confer multidrug resistan
ce to other antimitotic drugs that are used in cancer chemotherapy (Shan et
al., 1999). In addition to these resistance mechanisms, eukaryotic cells h
ave developed other protection mechanisms that involve enzymes that modify
electrophilic xenobiotics. To determine whether T138067 is a substrate for
such enzymatic detoxification pathways, a metabolism study was initiated. G
SH conjugation was shown to play a major role in T138067 metabolism. T13806
7-GSH conjugates were isolated from the culture media of T138067-treated ce
lls and the bile of mice treated i.v. with T138067. The major T138067-GSH d
egradation products were also isolated from these sources. F-19 NMR studies
of the metabolites showed that metabolic conversions occurred through subs
titution of the para fluorine atom in the pentafluorophenyl ring of T138067
. The T138067-GSH conjugate was also isolated from T138067 incubation buffe
r that had been exposed to mouse, rat, dog, or human liver slices, suggesti
ng that this mechanism is not species-specific. All three human glutathione
S-transferases (alpha, mu, and pi), which are expressed in a wide variety
of tissues including human tumors, were shown to metabolize T138067 effecti
vely in vitro. The combined data show that T138067 is being metabolized, in
vitro and in vivo, predominantly via a glutathione S-transferase-mediated
metabolic pathway.