Role of P-450 activity and glutathione levels in 1,2-dibromo-3-chloropropane tissue distribution, renal necrosis and in vivo DNA damage.
Treatments known to alter P-450 activity and glutathione levels were used to elucidate the involvement of P-450 and glutathione S-transferase metabolism in 1,2-dibromo-3-chloropropane (DBCP) organ toxicity in the rat. Phenobarbital pretreatment abolished DBCP-induced renal necrosis, whereas it had only a small effect on initial renal DNA damage. The DBCP levels in plasma and tissues were markedly reduced by phenobarbital pretreatment. Perdeuterated DBCP had much higher plasma and tissue levels than protio-DBCP in phenobarbital-pretreated animals, but perdeuteration was without effect in uninduced animals. This indicates that P-450 metabolism of DBCP is of major importance only in phenobarbital-pretreated animals. In order to study the effects of decreased glutathione levels on renal distribution and toxicity, rats were pretreated with either diethyl maleate or buthionine sulfoximine. The DBCP levels in plasma and tissues showed transitory elevations after diethyl maleate and buthionine sulfoximine pretreatment compared to the control situation. Despite the fact that diethyl maleate and buthionine sulfoximine pretreatments are known to block DBCP-induced DNA damage in vitro, these pretreatments did not significantly alter DBCP-induced renal necrosis nor DNA damage. Thus, a role for glutathione conjugation in DBCP-induced in vivo renal toxicity could not be established in the present study.
Låg
M
M
Department of Toxicology, National Institute of Public Health, Oslo, Norway.
Omichinski
J G
JG
Søderlund
E J
EJ
Brunborg
G
G
Holme
J A
JA
Dahl
J E
JE
Nelson
S D
SD
Dybing
E
E
D000818:Animals; D000969:Antinematodal Agents / Q000378:metabolism / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D007674:Kidney Diseases / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009336:Necrosis / Q000139:chemically induced; D011407:Propane / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D051381:Rats; D014018:Tissue Distribution
D000969:Antinematodal Agents; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; C007318:1,2-dibromo-3-chloropropane; D005978:Glutathione; D011407:Propane