Hepatic gene expression in protoporphyic Fech mice is associated with cholestatic injury but not a marked depletion of the heme regulatory pool.
BALB/c Fech(m1Pas) mice have a mutated ferrochelatase gene resulting in protoporphyria that models the hepatic injury occurring sporadically in human erythropoietic protoporphyria. We used this mouse model to study the development of the injury and to compare the dysfunction of heme synthesis with hepatic gene expression of liver metabolism, oxidative stress, and cellular injury/inflammation. From an early age expression of total cytochrome P450 and many of its isoforms was significantly lower than in wild-type mice. However, despite massive accumulation of protoporphyrin in the liver, expression of the main genes controlling heme synthesis and catabolism (Alas1 and Hmox1, respectively) were only modestly affected even in the presence of the cytochrome P450-inducing CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene. In contrast, in BALB/c mice exhibiting griseofulvin-induced hepatic protoporphyria with induction and destruction of cytochrome P450, both Alas1 and Hmox1 genes were markedly up-regulated. Other expression profiles in BALB/c Fech(m1Pas) mice identified roles for oxidative mechanisms in liver injury while modulated gene expression of hepatocyte transport proteins and cholesterol and bile acid synthesis illustrated the development of cholestasis. Subsequent inflammation and cirrhosis were also shown by the up-regulation of cytokine, cell cycling, and procollagen genes. Thus, gene expression profiles studied in Fech(m1Pas) mice may provide candidates for human polymorphisms that explain the sporadic hepatic consequences of erythropoietic protoporphyria.
Davies
Reginald
R
Medical Research Council, Toxicology Unit, Hodgkin Bldg., University of Leicester, Lancaster Rd, Leicester, LE1 9HN, UK.
Schuurman
Arenda
A
Barker
Colin R
CR
Clothier
Bruce
B
Chernova
Tatyana
T
Higginson
Fiona M
FM
Judah
David J
DJ
Dinsdale
David
D
Edwards
Richard E
RE
Greaves
Peter
P
Gant
Timothy W
TW
Smith
Andrew G
AG
D000375:Aging; D000818:Animals; D000935:Antifungal Agents / Q000633:toxicity; D002779:Cholestasis / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D015870:Gene Expression; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006118:Griseofulvin / Q000633:toxicity; D006418:Heme / Q000235:genetics / Q000378:metabolism*; D006420:Hemeproteins / Q000235:genetics / Q000378:metabolism; D015151:Immunoblotting; D008099:Liver / Q000473:pathology* / Q000502:physiology; D008297:Male; D051379:Mice; D046351:Protoporphyria, Erythropoietic / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D011524:Protoporphyrins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000935:Antifungal Agents; D006420:Hemeproteins; D011524:Protoporphyrins; D006118:Griseofulvin; D006418:Heme