Distribution of glutathione S-transferase isoforms in rat liver after induction by beta-naphthoflavone or 3-methylcholanthrene.
Regional differences in vulnerability to xenobiotic liver damage may relate to the distribution of the detoxication capacity of the glutathione S-transferases (GST). HPLC analysis of cell lysates obtained by digitonin infusion from either the periportal or the perivenous region revealed that the content of all the GST subunits investigated (1, 2, 3, 4 and 8) was higher in the perivenous region. The strongest perivenous dominance was observed for subunit 1 (Ya) and the alpha class appeared to be more zonated that the mu class. A similar perivenous dominance was observed by analysis of GST activity with either 1-chloro-2,4-dinitrobenzene (CDNB), 1,2-dichloronitrobenzene (DCNB) or trans-4-phenyl-3-buten-2-one (PBO) as substrate. In contrast, with cumene hydroperoxide (CuOOH) or tert-butyl hydroperoxide (tBOOH) as substrate a reciprocal twofold periportal dominance was observed. Induction by pretreatment with beta-naphthoflavone reduced or abolished the perivenous dominance of the alpha-subunits 1, 2 and 8. In contrast, after pretreatment with 3-methylcholanthrene, only the acinar gradient of subunits 2 (Yc) was abolished, while the strong perivenous gradient subunit 1 (Ya) was maintained and that of subunit 8 (Yk) increased. CDNB based assays demonstrated that beta-naphtoflavone treatment reduced (from 2.1 to 1.4) while 3-methyl cholanthrene enhanced (to 2.6) the perivenous/periportal GST activity ratio. Assays based on CuOOH or tBOOH indicated that neither the Se-dependent nor the Se-independent glutathione peroxidase activity nor its acinar distribution was affected by the inducers. These results demonstrated that although the expression of all investigated members of the alpha and mu classes is higher in the perivenous region, there are marked isozyme differences, the acinar gradient being particularly prominent for subunit 1 (Ya). The distinct difference in the acinar induction pattern of GST Ya between beta-naphthoflavone and 3-methylcholanthrene resembles that reported for cytochrome P450 (CYP1A1 and CYP1A2), also members of the aryl hydrocarbon (Ah) receptor genes, suggesting common regionally acting regulatory elements in the expression of these genes in the liver.
Sippel
H
H
Department of Forensic Medicine, University of Helsinki, Finland.
Lindros
K O
KO
Oinonen
T
T
D000818:Animals; D001555:Benzene Derivatives / Q000737:chemistry / Q000378:metabolism; D002273:Carcinogens / Q000633:toxicity*; D002851:Chromatography, High Pressure Liquid; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D004072:Digitonin / Q000494:pharmacology; D004137:Dinitrochlorobenzene / Q000737:chemistry / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000633:toxicity*; D005982:Glutathione Transferase / Q000096:biosynthesis* / Q000378:metabolism; D007527:Isoenzymes; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008748:Methylcholanthrene / Q000633:toxicity*; D016877:Oxidants / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D019324:beta-Naphthoflavone / Q000633:toxicity*
D001555:Benzene Derivatives; D002273:Carcinogens; D004137:Dinitrochlorobenzene; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D016877:Oxidants; D008748:Methylcholanthrene; D019324:beta-Naphthoflavone; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D005982:Glutathione Transferase; D004072:Digitonin; C007164:cumene hydroperoxide