Erythrocyte aminolevulinic acid dehydratase inhibition by cis-platin.
The effect of cis-platin on erythrocyte aminolevulinic acid dehydratase (ALAD) activity was studied in vivo and in vitro. Young male Wistar rats were treated with a single i.p. injection of cis-platin at 2.5, 5.0, and 10.0mg/kg dose. In addition, a single i.p. injection of lead nitrate (1.0mg/kg dose) was administered as positive control. Experiments in vitro were also performed to elucidate the possible mechanism of action. The aminolevulinic acid dehydratase was almost completely inhibited in vitro from 0.5mM concentration, and the IC(50) was stated at 0.265 mM, 20 times higher than lead (IC(50) stated at 0.013 mM). Reduced glutathione, partially but significantly, reactivated in vitro the enzyme treated with cis-platin (0.5 and 5.0mM), whereas zinc showed a positive, significant effect with the higher dose (5.0mM) only. On the contrary, inhibition caused by lead (0.005 mM) was partially, but significantly restored by reduced glutathione, and, almost completely, by zinc. The experiments in vivo show that cis-platin causes a dose- and time-dependent inhibition of ALAD activity with 5.0 and 10.0mg/kg dose, until 66 and 33% of the control activity 96 h after treatment, respectively. The results show that erythrocyte ALAD is sensitive to cis-platin and suggest that the mechanism of enzyme inhibition is a direct interaction with sulfhydryl groups, whereas zinc site appears involved with the higher doses only. This mechanism appears different from lead that prevalently inhibits ALAD removing zinc from the enzyme, other than interacting with sulfhydryl groups.
Department of Environmental Medicine and Public Health, University of Padua, Via Giustiniani 2, I-35128 Padua, Italy. andrea.trevisan@unipd.it
Andrea
A
Trevisan
Matteo
M
Borella-Venturini
Livio
L
Di Marco
Andrea
A
Fabrello
Monica
M
Giraldo
Edoardo
E
Zanetti
Christine
C
Marzano
Dolores
D
Fregona
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity*; D002945:Cisplatin / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors; D004912:Erythrocytes / Q000187:drug effects / Q000201:enzymology*; D005978:Glutathione / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007274:Injections, Intraperitoneal; D007854:Lead / Q000494:pharmacology; D008297:Male; D000623:Porphobilinogen Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007854:Lead; D000623:Porphobilinogen Synthase; D005978:Glutathione; D002945:Cisplatin