Modification of P450 activity and its effect on 1,2-dichlorobenzene toxicity in Fischer 344 rats.
This study examined the contribution of biotransformation by the mixed function oxidase system on hepatic and renal toxicity of 1,2-dichlorobenzene (1,2-DCB). Male Fischer 344 (F344) rats (190-250 g) were pretreated with phenobarbital (PB), beta-naphthoflavone (BNF), pyridine (PYR), piperonyl butoxide (PiBx) or vehicle prior to the administration of 2 or 3 mmol/kg of 1,2-DCB. Pair-fed control animals were treated with corn oil, (1 ml/kg). Plasma alanine amino-transaminase (ALT/GPT) was increased in a dose-dependent manner by 1,2-DCB. Pretreatment with PB, BNF or PB pretreatment prior to 1,2-DCB administration increased hepatic toxicity within 24 h. Toxicity was characterized by increased ALT/GPT activity and increased liver weight. Acute administration of 1,2-DCB produced renal alterations within 24 h. Renal toxicity was characterized by altered blood urea nitrogen (BUN) concentration and decreased renal cortical slice accumulation of p-aminohippurate (PAH) 24 h after injection of 3 mmol/kg 1,2-DCB. Pretreatment with PB, BNF or PYR increased the renal toxicity of 2 and 3 mmol/kg 1,2-DCB. Conversely, pretreatment with PiBx to inhibit P450 activity slightly decreased the hepatic and renal toxicity of 1,2-DCB. These results establish that the kidney was a target organ for 1,2-DCB toxicity and that the proximal tubule was a site of damage. Additionally, these studies indicate induction of P450 isozymes increased the hepatic and renal toxicity of 1,2-DCB. Further studies are needed to examine the specific role of P450 in generation of toxicity.
Valentovic
M A
MA
Department of Pharmacology, Marshall University School of Medicine, Huntington, WV 25755-9310.
Ball
J G
JG
Anestis
D
D
Madan
E
E
D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology; D001806:Blood Urea Nitrogen; D001835:Body Weight / Q000187:drug effects; D002722:Chlorobenzenes / Q000633:toxicity*; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D007306:Insecticides / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D006899:Mixed Function Oxygenases / Q000096:biosynthesis / Q000378:metabolism*; D009929:Organ Size / Q000187:drug effects; D010882:Piperonyl Butoxide / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D019324:beta-Naphthoflavone
D001571:Benzoflavones; D002722:Chlorobenzenes; D007306:Insecticides; D011725:Pyridines; D019324:beta-Naphthoflavone; C004726:2-dichlorobenzene; D006899:Mixed Function Oxygenases; D010882:Piperonyl Butoxide; C023666:pyridine