The role of oxidative metabolism in hexachlorobenzene-induced porphyria and thyroid hormone homeostasis: a comparison with pentachlorobenzene in a 13-week feeding study.
Hexachlorobenzene (HCB) induces a broad spectrum of effects including disturbances in the heme synthesis (porphyria) and in thyroid hormone homeostasis. For most of its effects, biotransformation of the parent compound seems to be a prerequisite. The present study was designed to assess the relevance of the oxidative metabolites in HCB-induced toxicity, with special attention to the role of the reactive tetrachlorobenzoquinone (TCBQ). To this end, toxicity and biotransformation of HCB were compared with those of pentachlorobenzene (PCB), since this chemical is oxidized to the same products as HCB, i.e., pentachlorophenol (PCP) and TCBQ. Female Wistar rats received diets containing different dose levels of HCB or PCB for 13 weeks, with or without cotreatment with triacetyloleandomycin (TAO), a selective inhibitor of cytochrome P450IIIA1/2. Rats treated with HCB (high dose) had significantly elevated levels of urinary porphyrins from the 4th week on and had a significant hepatic accumulation of porphyrins at the end of the study. Both urinary porphyrin excretion and hepatic porphyrin accumulation were greatly inhibited in rats receiving cotreatment with HCB and TAO. However, the inhibition of HCB-induced porphyria by TAO cannot be explained by a diminished formation of the highly reactive TCBQ, since rats treated with a high dose of PCB, which had a several fold higher urinary excretion of PCP and TCHQ compared to a high dose of HCB, did not develop porphyria. Instead, the present study points to the involvement of a putative reactive intermediate in the primary oxidative step in HCB-induced porphyria, since based on paired observations of individual rats, the degree of porphyria was correlated to a high degree with excretion of PCP, whereas correlation of porphyria with early excretion of TCHQ was much weaker. This finding fits well with the fact that the mechanisms of oxidation of HCB to PCP and PCB to PCP are different. Both HCB and PCB were oxidized to PCP and tetrachlorohydroquinone (TCHQ), the reduced analog of TCBQ. Cytochrome P450IIIA1/2 appears to be involved in the conversion of HCB and PCB, since cotreatment of TAO resulted in a strongly diminished urinary excretion of PCP and TCHQ. Treatment with HCB as well as PCB results in disturbances of retinoid and thyroid hormone homeostasis. These effects, which have also been reported after exposure to polychlorinated biphenyls, originate from interference of hydroxylated metabolites (notably PCP) with the plasma thyroxine transport protein, transthyretine, and since this metabolite is formed from both HCB and PCB, this results in the same toxicity for both compounds.
den Besten
C
C
Department of Toxicology, Agricultural University, Wageningen, The Netherlands.
Bennik
M H
MH
Bruggeman
I
I
Schielen
P
P
Kuper
F
F
Brouwer
A
A
Koeman
J H
JH
Vos
J G
JG
Van Bladeren
P J
PJ
D000818:Animals; D001711:Biotransformation; D001835:Body Weight / Q000187:drug effects; D002722:Chlorobenzenes / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity*; D004435:Eating / Q000187:drug effects; D005260:Female; D006581:Hexachlorobenzene / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity*; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D008099:Liver / Q000187:drug effects; D009929:Organ Size / Q000187:drug effects; D010084:Oxidation-Reduction; D010622:Phencyclidine / Q000652:urine; D011164:Porphyrias / Q000139:chemically induced* / Q000378:metabolism; D011166:Porphyrins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012176:Retinoids / Q000378:metabolism; D013963:Thyroid Hormones / Q000502:physiology*; D014217:Troleandomycin / Q000494:pharmacology
D002722:Chlorobenzenes; D011166:Porphyrins; D012176:Retinoids; D013963:Thyroid Hormones; D006581:Hexachlorobenzene; D014217:Troleandomycin; C003060:pentachlorobenzene; D010622:Phencyclidine