The relation between the oxidative biotransformation of hexachlorobenzene and its porphyrinogenic activity.
The relation between the major toxic effect of hexachlorobenzene, hepatic porphyria, and its oxidative biotransformation was studied in vivo, by observing the effect of modulating its biotransformation on the expression of porphyria. This modulation was achieved by selective in vivo inhibition of the major cytochrome P450 isoenzyme involved in both the hydroxylation of hexachlorobenzene and its primary oxidative metabolite, pentachlorophenol. The involvement of this isoenzyme, cytochrome P450p, was established by in vitro biotransformation studies using microsomes derived from rats treated with various inducers of cytochrome P450 isoenzymes and selective in vitro inactivation of cytochrome P450p by triacetyloleandomycin (TAO), resulting in a strong inhibition of the microsomal conversion of hexachlorobenzene and pentachlorophenol. In vivo inactivation of cytochrome P450p was achieved by coadministration of hexachlorobenzene and TAO. Female rats which were treated with this diet for 10 weeks showed a strongly diminished urinary excretion of the major oxidative metabolites, pentachlorophenol and tetrachloro-1,4-hydroquinone, as compared to rats treated with hexachlorobenzene alone. The TAO coadministration was found to result in complexation of 70% of the total amount of hepatic microsomal cytochrome P450. The group treated with hexachlorobenzene alone displayed a 600-fold increase in the amount of hepatic porphyrins, whereas an almost complete absence of hepatic porphyrins was observed after administration of hexachlorobenzene together with TAO. The urinary excretion of porphyrins was also significantly lowered by cotreatment with TAO. A strong correlation was found to exist between the amount of porphyrins excreted and the amount of oxidative metabolites excreted, as a function of exposure time. Glucuronidation of pentachlorophenol was observed to an average extent of 30%. This percentage was not influenced by either TAO or phenobarbital. These results suggest that oxidative biotransformation, and thus the formation of the very reactive tetrachloro-1,4-benzoquinone, is directly related to the porphyrinogenic action of hexachlorobenzene.
van Ommen
B
B
TNO-CIVO Toxicology and Nutrition Institute, Department of Biological Toxicology, Zeist, The Netherlands.
Hendriks
W
W
Bessems
J G
JG
Geesink
G
G
Müller
F
F
van Bladeren
P J
PJ
D000818:Animals; D001711:Biotransformation; D056486:Chemical and Drug Induced Liver Injury; D002722:Chlorobenzenes / Q000493:pharmacokinetics*; D065607:Cytochrome P-450 Enzyme Inhibitors; D005260:Female; D006581:Hexachlorobenzene / Q000493:pharmacokinetics* / Q000633:toxicity; D006873:Hydroquinones / Q000378:metabolism; D066298:In Vitro Techniques; D008107:Liver Diseases / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D010084:Oxidation-Reduction; D010416:Pentachlorophenol / Q000378:metabolism; D011164:Porphyrias / Q000139:chemically induced* / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D014217:Troleandomycin / Q000494:pharmacology
D002722:Chlorobenzenes; D065607:Cytochrome P-450 Enzyme Inhibitors; D006873:Hydroquinones; D006581:Hexachlorobenzene; C044578:2,3,5,6-tetrachlorohydroquinone; D014217:Troleandomycin; D010416:Pentachlorophenol