Gamma-glutamyltransferase induction by glucocorticoids in rat liver: age-dependence, time-dependence, dose-dependence, and intralobular distribution.
Postnatal responsiveness of rat-liver gamma-glutamyltransferase (GGT) to glucocorticoids (GC) has been defined by investigating: age-dependence, time-dependence, hormonal dose-dependence, and lag-time of the enzyme re-expression; half-life of the induced enzyme activity; dynamics of the enzyme reappearance in the liver tissue. Hydrocortisone-acetate (HC) or dexamethasone (DEX) were administered to the animals starting 1, 2, 3, 4, or 5 d before killing, at the doses of 25 micrograms or 1 microgram/(g b. w. x d), respectively. In 14 d old rats, after a lag-time of about 20 h (DEX) or 30 h (HC), GGT activity progressively increased up to 38 and 31 times the control value, respectively, at 5th d; the enzyme re-expression was linearly hormone dose-dependent; half-life of the induced enzyme activity was about 36 h. In 21 d old rats, GGT re-induction behaved as in 14 d old animals, except that the induced activity was about half that of each correspondent treatment. In 28 d old rats, a very low but significant GGT activity was re-expressed only after hormonal treatments longer than 48 h. In 35 and 77 d old rats, significant GGT activity was never re-induced. GGT was re-expressed in liver parenchyma, with a defined space-course. In 14 d old rats, GGT reappeared first in periportal areas, then in acinar zone 1, finally in acinar zone 2. While the animals were ageing, GGT re-expression occurred to lesser and lesser extents in liver tissues, because of a progressive space-restriction from acinar zones 1 and 2 to zone 1 and finally, in 35 d old rats, to periportal areas. In adults, GGT was re-expressed only by rare hepatocytes in periportal spaces. Acinar zone-3 hepatocytes did never re-express GGT, irrespectively of the animal age. Thus, 2 rat hepatocyte populations could be distinguished (1 responsive, the other unresponsive to GC for GGT re-expression), the relative proportion of which changes in favour of the unresponsive one while the animal ages. Hepatic GGT re-induction by GC, occurring after a long lag-time, does not follow the typical model of hormonal induction. Previous permissive cell changes seem to be required. Hepatocyte-GGT re-expression by GC appears to be inversely correlated with the differentiation level and the cytochrome P-450 amount (activity) of the cell as limiting factors for the triggering of the enzyme induction.
Tongiani
R
R
Instituto di Patologia Generale, Università degli Studi di Pisa, Italy.
Paolicchi
A
A
D000375:Aging / Q000378:metabolism*; D000818:Animals; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage / Q000494:pharmacology*; D006854:Hydrocortisone / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors; D014018:Tissue Distribution; D005723:gamma-Glutamyltransferase / Q000096:biosynthesis*
D005938:Glucocorticoids; C021650:hydrocortisone acetate; D003907:Dexamethasone; D005723:gamma-Glutamyltransferase; D006854:Hydrocortisone