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Gender dimorphic formation of Mallory‐Denk bodies and the role of xenobiotic metabolism and oxidative stress
Author(s) -
Snider Natasha T,
Hanada Shinichiro,
Brunt Elizabeth M,
Hollenberg Paul F,
Omary M. Bishr
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.757.7
Subject(s) - oxidative stress , cytochrome p450 , hepatocyte , chemistry , sexual dimorphism , cyp2e1 , metabolite , lipid peroxidation , lipid metabolism , biochemistry , oxidative phosphorylation , microbiology and biotechnology , metabolism , biology , endocrinology , in vitro
Mallory‐Denk bodies (MDBs) are hepatocyte cytoplasmic inclusions associated with alcoholic steatohepatitis. Understanding the significance of MDBs and devising ways of manipulating their formation has clinical relevance to protein aggregation diseases beyond liver. Current appreciation of MDBs comes from established models whereby feeding mice the porphyrinogenic compound 3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine (DDC) induces inclusions resembling human MDBs. Given the significant gender differences in predisposition to liver injury, we hypothesized that gender is an important factor in MDB formation. Male DDC‐fed mice formed significantly more MDBs, which correlated with hepatocyte apoptosis, fat globules and lipid peroxidation. Female mice had significantly less MDBs and oxidative stress, but elevated ductular reaction and protoporphyrin‐IX accumulation. There were significant gender differences in the expression and activity of cytochrome‐P450 (CYP) enzymes before and after DDC treatment, resulting in differences in formation of a CYP3A‐derived DDC metabolite, which may contribute to oxidative stress. The data provide a mechanistic explanation for the gender dimorphic formation of MDBs and aid in understanding how inter‐individual differences in microsomal metabolism may alter susceptibility to diseases underlying protein aggregation. Support: DK52951 and UL1RR024986.