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Here we investigate the development of uroporphyria as a function of CYP1A2 and iron levels in the liver of mice having a common C57BL\/6 genetic background. We compared\n                      <jats:italic toggle=\"yes\">Cyp1a2(\u2212\/\u2212)<\/jats:italic>\n                      knockout mice,\n                      <jats:italic toggle=\"yes\">Cyp1a2(+\/\u2212)<\/jats:italic>\n                      heterozygotes,\n                      <jats:italic toggle=\"yes\">Cyp1a2(+\/+)<\/jats:italic>\n                      wild type, and\n                      <jats:italic toggle=\"yes\">Cyp1a2(+\/+)<\/jats:italic>\n                      mice pretreated with a low dose of 3,3',4,4',5-pentachlorobiphenyl (PCB126) (4 \u03bcg\/kg).\n                      <jats:italic toggle=\"yes\">Cyp1a2(+\/\u2212)<\/jats:italic>\n                      mice contain about 60% of the hepatic CYP1A2 content of\n                      <jats:italic toggle=\"yes\">Cyp1a2(+\/+)<\/jats:italic>\n                      mice, and the PCB126-pretreated\n                      <jats:italic toggle=\"yes\">Cyp1a2(+\/+)<\/jats:italic>\n                      mice have about twice the wild-type levels of CYP1A2. ALA- and iron-treated\n                      <jats:italic toggle=\"yes\">Cyp1a2(+\/+)<\/jats:italic>\n                      mice are known to accumulate hepatic uroporphyrin; this accumulation was increased 7-fold by pretreatment with the low dose of PCB126. ALA- and iron-treated\n                      <jats:italic toggle=\"yes\">Cyp1a2(+\/\u2212)<\/jats:italic>\n                      heterozygote mice accumulated no uroporphyrin in 4 weeks, but by 8 weeks accumulated significant amounts of uroporphyrin. As previously reported, the ALA- and iron-treated\n                      <jats:italic toggle=\"yes\">Cyp1a2(\u2212\/\u2212)<\/jats:italic>\n                      knockout mouse has no CYP1A2 and exhibits no detectable uroporphyrin accumulation. Iron dose-response curves in ALA- and PCB126-treated\n                      <jats:italic toggle=\"yes\">Cyp1a2(+\/+)<\/jats:italic>\n                      mice showed that hepatic iron levels greater than 850 \u03bcg\/g liver were required to produce significant uroporphyrin accumulation in the liver. Other measures of hepatic effects of iron (iron-response element-binding protein [IRP]-iron response element [IRE] binding activity and accumulation of protoporphyrin from ALA) decreased when the level of iron was considerably lower than 850 \u03bcg\/g liver. At low iron doses, accumulation of iron was principally in Kupffer cells, whereas at the higher doses (required to stimulate uroporphyrin accumulation), more iron was found in parenchymal cells. We conclude that small changes in hepatic CYP1A2 levels can dramatically affect uroporphyria in C57BL\/6 mice, providing the animals have been sufficiently loaded with iron; these data might be clinically relevant to acquired (sporadic) porphyria cutanea tarda, because humans show greater than 60-fold genetic differences in hepatic basal CYP1A2.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1053\/jhep.2002.32487","type":"journal-article","created":{"date-parts":[[2002,8,24]],"date-time":"2002-08-24T23:46:10Z","timestamp":1030232770000},"page":"912-921","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":31,"title":["Uroporphyria in mice: Thresholds for hepatic CYP1A2 and iron"],"prefix":"10.1097","volume":"35","author":[{"given":"Nadia","family":"Gorman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerry L.","family":"Ross","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heidi S.","family":"Walton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William J.","family":"Bement","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliana G.","family":"Szakacs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Glenn S.","family":"Gerhard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy P.","family":"Dalton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel W.","family":"Nebert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard S.","family":"Eisenstein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline F.","family":"Sinclair","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter R.","family":"Sinclair","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"10.1053\/jhep.2002.32487-BIB1|cit1","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1055\/s-2007-1007142","article-title":"Porphyria cutanea tarda","volume":"18","author":"Elder","year":"1998","journal-title":"Semin Liver Dis"},{"key":"10.1053\/jhep.2002.32487-BIB2|cit2","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1002\/hep.510270142","article-title":"Alcohol intake and porphyria cutanea 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