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Fucosyl transferases: Differential plasma and tissue alterations in hepatocellular carcinoma
121
122
FUCOSYL
TRA.‘M=ERASES:
AUD TISSUE CARCINOMA
ALTERATIONS
Hutchinson.
L&r
Unit.
The
IN
PLASMA
ONE YEAR OF THERAPY HEPATITIS WITH RECOMBIN:\:.
HEPATOCELLULAR
LYMPHOBLASTOID
W.L
Dentiswy.
DIFFERENTIAL
M-O
Hospital
& School of Medicine
&
London SE5 9RS.
fucose
composition
(tidlinkcd)
of
sevcrnl
nonA. nonB/C CHRO?JIC a-& IWERFEROS (r-1Fi-G)OR
a INTERFERON (L-IFWJ
.G@o ?? G.Bcllsd.~ (Milan). StAnna Hospital (Coma). Italy.
LJU. P.1. Johnson & R. Williams
King’s College
OF
Liver Unirs Wguuda
Hospiti
of IFNs on chronic non-A. non-B kpxids. To eva~ ‘c d8eeffiiy fmm May 19b 52 consecutive oaiints were mndomlv &!cxcd ID no lherapy 6 r- m drn for oneyear~andfollowed for at I& six monlhs alter uwmenl DFN dosage 3 MU/day for 15 days. ~Sen3 hlU on alwmxive days for 45 days. finally 3 MU three times per week for IO mombs). Sevent-sevenper cent WQCan&HCV positive (onho).
serum
:
gl}copmteins. most notably AFF’. is substantially altered in patients v+ith hepawellular carcinoma (HCC). In seeking an ex@onalion for these changes, w ha= examined the activities of Golgiderixd fucosyl transferases in plasma and tissue samples of aflccted palients. The aclivity ofocldfucose transfcrase ws si_eniticantlyelevated (p~O.025) in plasma from 35 HCC patienls (SO k
4Ofmolrrhr,‘ml)
compared
with those from cirrhotic
impmvenlcnt OE 15R9 -pmlIlmosis - k&Iv necrosis 1s/z9* - porwl inflam. 14/29 4RO _ HAI (Ku&II) 20/29’ 7fzo antibcdiis to IFN mimr side e&ecu 2$% ‘sign. dilf.vs non uwcd group (Fisher Test).
and
normal subjects (3 + 7 and 36 + 7fmolesihrlml respectiwly. n=lO each). Similar findings resulted for the&l-2 and -1-3 activities. These chmges appear specific for fucose as Ihe similarly Golgjdenwd galactosyl transfenw was increased to the same extent m HCC and cirrhotic padents (1400 + 425 and 1570 +2~Ofmoleshr!m~ respectively). Within turnour tissue Ihe actidty
old-lbfucosyl
that in cirrhotic patients (tlpicall;. respectiwly) lower.
transferase
non-lumour
was invariably greater
than
and oil-3
10/15’ IO/W S/l5 13/15’ O/15 14/IY
Followmg CCS~JIHXI of therapy ALT relapsed in 70% and 586 of respcmdcn. respectively 10 r- and L-IFN. No diffcrenca could bc found
tissue taken from the same HCC
!umcur 3rd non-turnour: 5 and 2 fmoles/hrimg
ahereas the al-2
6/1J 9114 4115 1115
accordinglu sex. age, previoustransfusion.dcreclionof aui-HCV.
activities were markedly
: 1)IF3
Conclusions signi&auly reduces~emm ALT level and ameliomws necm-inflammation activity in the liver, 2) lhae is a trend mward bwer responseto 1-IFN rhyl D r-IFN: 3) 10avoid the frequent relapws obrrved at !hc end d ueaunenr.differem schcdulcsshouldbc uicd.
These chanter in the production and Iransport of fucoq4 transfcmses m HCC patients may explain the altered protein fucosylation.
124 INHIEITIDN OF CYCLOSPDRIN A (CSA)-INDUCED LIPID PEROXIDATIDN (LPD) AND CYTDCHRM P-450 DECREASE IN HUMAN LIVER MICROSOWES BY EDTA G. :nselmann, U. I. Medical Clinic,
Nellessen, University
H.Th. Heidemann, of Kiel, FRG
The present in vitro study using human liver tissue was performed to investigste the effect of EDTA on CsA-induced LPD and cytochrome P-450 concentration in isolated liver microsones E:periments rere carried out for 60 min at 37 C. pH 7.4, with the following CsA concentrations: lD-30-100 rg/ ml in the presence or absence of EDTA (0.1 rnl.4) or of reduced lipoid acid (LA; 1nW. L?O was monitored measuring the wmunt of malondialdehyde (l,!DA). CsA caused a concentration dependent increase of MDA (13-fold) which was combined with a decrease of the cytochrome P-450 concentration to 13% of the contiol value. In the presence of EDTA or LA lipid peroxidstion was significantly inhibited, MDA production due to CsA increased only 3-fold and in turn the decrease of cytochrome P-450 concentration in response to CsA was significantly inhibited. In sumnary the results denmnstrate that CsA induced LPO in human liver microsomes with a concomitant decrease of the cytochrome P-450 concentration mdy be inhibited by the iron chelator EDTA or the antioxidant LA, suggesting that the drug may cause iron release participating in CsA-induced LPO and hepatotoxicity.
s31
122
FUCOSYL
TRA.‘M=ERASES:
AUD TISSUE CARCINOMA
ALTERATIONS
Hutchinson.
L&r
Unit.
The
IN
PLASMA
ONE YEAR OF THERAPY HEPATITIS WITH RECOMBIN:\:.
HEPATOCELLULAR
LYMPHOBLASTOID
W.L
Dentiswy.
DIFFERENTIAL
M-O
Hospital
& School of Medicine
&
London SE5 9RS.
fucose
composition
(tidlinkcd)
of
sevcrnl
nonA. nonB/C CHRO?JIC a-& IWERFEROS (r-1Fi-G)OR
a INTERFERON (L-IFWJ
.G@o ?? G.Bcllsd.~ (Milan). StAnna Hospital (Coma). Italy.
LJU. P.1. Johnson & R. Williams
King’s College
OF
Liver Unirs Wguuda
Hospiti
of IFNs on chronic non-A. non-B kpxids. To eva~ ‘c d8eeffiiy fmm May 19b 52 consecutive oaiints were mndomlv &!cxcd ID no lherapy 6 r- m drn for oneyear~andfollowed for at I& six monlhs alter uwmenl DFN dosage 3 MU/day for 15 days. ~Sen3 hlU on alwmxive days for 45 days. finally 3 MU three times per week for IO mombs). Sevent-sevenper cent WQCan&HCV positive (onho).
serum
:
gl}copmteins. most notably AFF’. is substantially altered in patients v+ith hepawellular carcinoma (HCC). In seeking an ex@onalion for these changes, w ha= examined the activities of Golgiderixd fucosyl transferases in plasma and tissue samples of aflccted palients. The aclivity ofocldfucose transfcrase ws si_eniticantlyelevated (p~O.025) in plasma from 35 HCC patienls (SO k
4Ofmolrrhr,‘ml)
compared
with those from cirrhotic
impmvenlcnt OE 15R9 -pmlIlmosis - k&Iv necrosis 1s/z9* - porwl inflam. 14/29 4RO _ HAI (Ku&II) 20/29’ 7fzo antibcdiis to IFN mimr side e&ecu 2$% ‘sign. dilf.vs non uwcd group (Fisher Test).
and
normal subjects (3 + 7 and 36 + 7fmolesihrlml respectiwly. n=lO each). Similar findings resulted for the&l-2 and -1-3 activities. These chmges appear specific for fucose as Ihe similarly Golgjdenwd galactosyl transfenw was increased to the same extent m HCC and cirrhotic padents (1400 + 425 and 1570 +2~Ofmoleshr!m~ respectively). Within turnour tissue Ihe actidty
old-lbfucosyl
that in cirrhotic patients (tlpicall;. respectiwly) lower.
transferase
non-lumour
was invariably greater
than
and oil-3
10/15’ IO/W S/l5 13/15’ O/15 14/IY
Followmg CCS~JIHXI of therapy ALT relapsed in 70% and 586 of respcmdcn. respectively 10 r- and L-IFN. No diffcrenca could bc found
tissue taken from the same HCC
!umcur 3rd non-turnour: 5 and 2 fmoles/hrimg
ahereas the al-2
6/1J 9114 4115 1115
accordinglu sex. age, previoustransfusion.dcreclionof aui-HCV.
activities were markedly
: 1)IF3
Conclusions signi&auly reduces~emm ALT level and ameliomws necm-inflammation activity in the liver, 2) lhae is a trend mward bwer responseto 1-IFN rhyl D r-IFN: 3) 10avoid the frequent relapws obrrved at !hc end d ueaunenr.differem schcdulcsshouldbc uicd.
These chanter in the production and Iransport of fucoq4 transfcmses m HCC patients may explain the altered protein fucosylation.
124 INHIEITIDN OF CYCLOSPDRIN A (CSA)-INDUCED LIPID PEROXIDATIDN (LPD) AND CYTDCHRM P-450 DECREASE IN HUMAN LIVER MICROSOWES BY EDTA G. :nselmann, U. I. Medical Clinic,
Nellessen, University
H.Th. Heidemann, of Kiel, FRG
The present in vitro study using human liver tissue was performed to investigste the effect of EDTA on CsA-induced LPD and cytochrome P-450 concentration in isolated liver microsones E:periments rere carried out for 60 min at 37 C. pH 7.4, with the following CsA concentrations: lD-30-100 rg/ ml in the presence or absence of EDTA (0.1 rnl.4) or of reduced lipoid acid (LA; 1nW. L?O was monitored measuring the wmunt of malondialdehyde (l,!DA). CsA caused a concentration dependent increase of MDA (13-fold) which was combined with a decrease of the cytochrome P-450 concentration to 13% of the contiol value. In the presence of EDTA or LA lipid peroxidstion was significantly inhibited, MDA production due to CsA increased only 3-fold and in turn the decrease of cytochrome P-450 concentration in response to CsA was significantly inhibited. In sumnary the results denmnstrate that CsA induced LPO in human liver microsomes with a concomitant decrease of the cytochrome P-450 concentration mdy be inhibited by the iron chelator EDTA or the antioxidant LA, suggesting that the drug may cause iron release participating in CsA-induced LPO and hepatotoxicity.
s31