Ther
apy with the or
al
antidi
abetic
agent troglit
azone (Rezulin) h
as been
associ
ated withc
ases of severe hep
atotoxicity
and drug-induced liver f
ailure, which led to the recent withdr
aw
alof the product from the U.S. m
arket. While the mech
anism of this toxicity rem
ains unknown,it is possible th
at chemic
ally re
active met
abolites of the drug pl
ay
a c
aus
ative role. In
an effortto
address this possibility, this study w
as undert
aken to determine whether troglit
azoneundergoes met
abolism in hum
an liver microsom
al prep
ar
ations to electrophilic intermedi
ates.Following incub
ation of troglit
azone with hum
an liver microsomes
and with cDNA-expressedcytochrome P450 isoforms in the presence of glut
athione (GSH),
a tot
al of five GSH conjug
ates(M1-M5) were detected
and identified tent
atively by LC-MS/MS
an
alysis. In two c
ases (M1
and M5), the structures of the
adducts were confirmed by NMR spectroscopy
and/or bycomp
arison with
an
authentic st
and
ard prep
ared by synthesis. The form
ation of GSH conjug
atesM1-M5 reve
aled the oper
ation of two distinct met
abolic
activ
ation p
athw
ays for troglit
azone,one of which involves oxid
ation of the substituted chrom
ane ring system to
a re
active
o-quinonemethide deriv
ative, while the second involves
a novel oxid
ative cle
av
age of the thi
azolidinedione(TZD) ring, potenti
ally gener
ating highly electrophilic
ages/gifch
ars/
alph
a.gif" BORDER=0>-ketoisocy
an
ate
and sulfenic
acidintermedi
ates. When troglit
azone w
as
administered or
ally to
a r
at, s
amples of bile were foundto cont
ain GSH conjug
ates which reflected the oper
ation of these s
ame met
abolic p
athw
ays invivo. The finding th
at met
abolism of the TZD ring of troglit
azone w
as c
at
alyzed selectively byP450 3A enzymes is signific
ant in light of the recent report th
at troglit
azone is
an inducer ofthis isoform in hum
an hep
atocytes. The implic
ations of these results
are discussed in the contextof the potenti
al for troglit
azone to cov
alently modify hep
atic proteins
and to c
ause oxid
ativestress through redox cycling processes, either of which m
ay pl
ay
a role in drug-induced liverinjury.