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Progressive Glomerulonephritis and Histiocytic Sarcoma Associated with Macrophage Functional Defects in CYP1B1-Deficient Mice

The National Institute of Allergy and Infectious Diseases, NIH and SoBran, Inc., Bethesda, Maryland 20892-8135, USA, jw116y{at}nih.gov

Nikolay P. Nikolov

National Institute of Arthritis and Musculoskeletal and Skin Diseases, DHHS, Bethesda, Maryland 20892, USA

Jolynne R. Tschetter

Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA

Jeffrey B. Kopp

National Institute of Diabetes & Digestive & Kidney Diseases, NIH, DHHS, Bethesda, Maryland 20892, USA

Frank J. Gonzalez

Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA

Shioko Kimura

Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA

Richard M. Siegel

National Institute of Arthritis and Musculoskeletal and Skin Diseases, DHHS, Bethesda, Maryland 20892, USA

The cytochrome P450 CYP1B1 enzyme metabolically activates polycyclic aromatic hydrocarbons and is a major P450 isoenzyme in human monocytes and macrophages. We have shown previously that mice deficient in CYP1B1 were resistant to induced tumors after 7,12-dimethylbenz[a]anthracene exposure. The pathology of aging CYP1B1 null mice on a B6; 129 background was studied in groups of 29 males and 30 females. By 12 months, 50% of the female mice had developed a unusual progressive glomerulonephritis while males had similar renal lesions later in life. This disease followed a sequence of proliferative, membranoproliferative and sclerotic glomerulonephritis. Anti-DNA antibodies were found in the blood of the mice along with immune deposits containing immunoglobulins in subepithelial locations of the glomerular basement membrane. The lesions were unlike those found in aging wild-type B6;129 mice or mice of other strains. We found that macrophages from CYP1B1-null mice were impaired in the phagocytosis of apoptotic, necrotic, and opsonized cells. This suggests a generalized defect in the phagocytic activity of CYP1B1-null mouse macrophages. Male mice also developed a high incidence (62—64%) of histiocytic sarcomas. Our study provides evidence that deficiency of CYP1B1 can play a role in the development of glomerular disease, normal processing of catabolic DNA and tumors of the mononuclear phagocyte system. The function of CYP1B1 in histiocytes and macrophages may involve both self-tolerance and tumor suppression.

Key Words: CYP1B1 • knockout mice • glomerulonephritis • mice • histiocytic sarcoma • macrophages • phagocytosis • autoimmune disease.

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