title: Comparative studies on the inducing effects of cobalt chloride and co-protoporphyrin on hepatic ornithine decarboxylase and heme oxygenase in rats.
abstract: Co-protoporphyrin, like Co2+, produced a significant and persistent induction of hepatic ornithine decarboxylase (ODC) as well as its known inducing effect on heme oxygenase and the decreasing effects on drug-metabolizing enzymes. The induction of ODC and heme oxygenase by Co-protoporphyrin occurred dose-dependently with the lowest effective dose of 6.25 mumol/kg. Although Co-protoporphyrin produced similar effects on ODC and heme oxygenase to Co2+, there were differences in the mode of ODC induction. In particular, pretreatment with diethyl maleate failed to augment the induction of ODC by Co-protoporphyrin. Moreover, multiple administrations of Co2+, but not Co-protoporphyrin, caused super-additive induction of ODC to about 1000-fold over the controls. This super-additive induction of ODC by Co2+ was dependent on the doses and time intervals between two administrations. In parallel with a large induction of ODC evoked by two administrations of Co2+, hepatic putrescine content was increased markedly, while spermine content was decreased as compared to the control levels. Pretreatment with Co2+ led to super-additive induction of ODC by subsequent administration of the metal ion itself or diethyl maleate, but not by other ODC inducers, such as Co-protoporphyrin and thioacetamide, and not by subsequent partial hepatectomy. Under these experimental conditions, the magnitudes of heme oxygenase induction were similar. ODC induced by two doses of Co2+ was insensitive to exogenous putrescine, but sensitive to alpha-difluoromethylornithine and 1,3-diaminopropane. These findings add new insight into the effects of Co2+ and Co-protoporphyrin on hepatic polyamine metabolism; and the results suggest that the metal ion could cause extensive derangement of the ODC regulatory system in a manner different from the metalloporphyrin.
authors.affiliation: Department of Biochemical Toxicology, School of Pharmaceutical Sciences, Showa University, Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Numazawa
authors.forename: T
authors.initials: T
authors.lastname: Oguro
authors.forename: T
authors.initials: T
authors.lastname: Yoshida
authors.forename: Y
authors.initials: Y
authors.lastname: Kuroiwa
mesh_terms: D000818:Animals; D003035:Cobalt / Q000494:pharmacology*; D003959:Diamines / Q000494:pharmacology; D000518:Eflornithine / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis*; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D008298:Maleates / Q000494:pharmacology; D006899:Mixed Function Oxygenases / Q000096:biosynthesis* / Q000378:metabolism; D009955:Ornithine Decarboxylase / Q000096:biosynthesis*; D011073:Polyamines / Q000378:metabolism; D011166:Porphyrins / Q000494:pharmacology*; D011524:Protoporphyrins / Q000494:pharmacology*; D011700:Putrescine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
chemical_list: D003959:Diamines; D008298:Maleates; D011073:Polyamines; D011166:Porphyrins; D011524:Protoporphyrins; D003035:Cobalt; C009475:trimethylenediamine; D006899:Mixed Function Oxygenases; D006419:Heme Oxygenase (Decyclizing); D009955:Ornithine Decarboxylase; C018021:cobaltous chloride; C014476:diethyl maleate; D011700:Putrescine; D000518:Eflornithine