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.