The dysfunction of hepatic
heme synthesis by 2,3,7,8-tetrachlordibenzo-
p-dioxin (
TCDD) in mice, enhanced by
iron, leads to accumulation of
uroporphyrins I and III (uroporphyria) and resembles the human disorder
porphyria cutanea tarda (PCT) precipitated by alcohol and estrogenic drugs. Although consequences of
TCDD are considered entirely dependent on the
aryl hydrocarbon receptor (AHR), this is not proven for uroporphyria. Administration of
TCDD (75 microg/kg) caused uroporphyria in susceptible C57BL/6J mice with high-affinity AHR after 5 weeks (>600-fold increase in hepatic
uroporphyrins). Transcriptomics showed significant modified gene expressions for intermediary,
heme, and
iron metabolism as well as for oxidative stress and cell injury. Resistant low-affinity AHR DBA/2 mice (no increase in
porphyrins) showed far fewer changes. At this dose of
TCDD, persistent up-regulation of some traditional AH battery genes occurred in both strains. Essentiality of AHR was demonstrated with C57BL/6 Ahr knockout mice. Elevation of hepatic
uroporphyrins was 964-fold in Ahr (+/+) mice, lower in Ahr (+/-) (60-fold), but undetectable with Ahr (-/-) . Consistent with an oxidative mechanism,
iron overload enhanced
porphyria as well as general liver injury in Ahr (+/+) and Ahr (+/-) mice but had no interactive effect in Ahr (-/-) . In contrast, when
iron-treated mice received, instead of
TCDD, the
heme precursor 5-aminolevulinic
acid (ALA), causing uroporphyia in Ahr (+/+) mice (242-fold rise in
uroporphyrins), elevation of
uroporphyrins I and III (42-fold) also occurred in Ahr (-/-) mice and was seemingly associated with AHR-independent expression of
Cyp1a2. The findings prove that AHR is a key factor in
porphyria induced in mice by
TCDD. However, in other models of human PCT, participation of AHR may not be an essential requirement.