title: Paradoxical attenuation of autoimmune hepatitis by oral isoniazid in wild-type and N-acetyltransferase-deficient mice.
abstract: Isoniazid (INH) treatment can cause serious liver injury and autoimmunity. There are now several lines of evidence that INH-induced liver injury is immune mediated, but this type of liver injury has not been reproduced in animals, possibly because immune tolerance is the dominant response of the liver. In this study, we immunized mice with isonicotinic acid (INA)-modified proteins and Freund's adjuvant, which led to mild experimental autoimmune hepatitis (EAH) with an increase in cells staining positive for F4/80, CD11b, CD8, CD4, CD45R, and KI67. We expected that subsequent treatment of mice with oral INH would lead to more serious immune-mediated liver injury, but paradoxically it markedly attenuated the EAH caused by immunization with INA-modified hepatic proteins. In addition, patients of the slow acetylator phenotype are at increased risk of INH-induced liver injury. Treatment of arylamine N-acetyltransferase-deficient Nat1/2(-/-) mice with INH for up to 5 weeks produced mild increases in glutamate and sorbitol dehydrogenase activities, but not severe liver injury. Female Nat1/2(-/-) mice treated with INH for 1, 3, or 7 days developed steatosis, an increase in Oil Red O staining, and abnormal mitochondrial morphology in the liver. A decrease in M1 and an increase in M2a and M2b macrophages was observed in female Nat1/2(-/-) mice treated with INH for 1, 3, or 7 days; these changes returned to baseline levels by day 35. These data indicate that INH has immunosuppressive effects, even though it is also known to induce autoantibody production and a lupus-like autoimmune syndrome in humans.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Medicine (I.M., D.G., J.U.), and Department of Pharmaceutical Sciences, Faculty of Pharmacy (P.C., D.G., J.U.), University of Toronto, Toronto, Ontario, Canada; and Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Departamento de Toxicología, Distrito Federal, México (L.V.).
authors.forename: Imir G
authors.initials: IG
authors.lastname: Metushi
authors.forename: Ping
authors.initials: P
authors.lastname: Cai
authors.forename: Libia
authors.initials: L
authors.lastname: Vega
authors.forename: Denis M
authors.initials: DM
authors.lastname: Grant
authors.forename: Jack
authors.initials: J
authors.lastname: Uetrecht
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001191:Arylamine N-Acetyltransferase / Q000172:deficiency*; D005234:Fatty Liver / Q000139:chemically induced / Q000201:enzymology / Q000276:immunology; D005260:Female; D019693:Hepatitis, Autoimmune / Q000188:drug therapy* / Q000201:enzymology* / Q000276:immunology; D007538:Isoniazid / Q000008:administration & dosage* / Q000009:adverse effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D001191:Arylamine N-Acetyltransferase; C524206:Nat2 enzyme, mouse; D007538:Isoniazid