Mechanisms underlying methotrexate-induced pulmonary toxicity.
BACKGROUND
Methotrexate (MTX) has been widely used for the treatment of inflammatory diseases and rheumatoid arthritis, as well as a variety of tumors. However, MTX-induced pulmonary toxicity is a serious and unpredictable side effect of the therapy, which includes allergic, cytotoxic or immunologic reactions, and is a major clinical problem.


OBJECTIVE
To summarize the mechanisms of action involved in MTX-induced pulmonary toxicity.


METHODS
We reviewed the literature describing MTX-induced adverse pulmonary effects and the mechanisms of action underlying MTX-induced pulmonary toxicity.


CONCLUSIONS
The mechanisms underlying MTX toxicity are complex. The clinical effects may be attributable to both the anti-inflammatory and immunosuppressive effects of MTX. The mechanisms causing the side effects of MTX include mutation of the genotype, inhibition of transport, MTX-polyglutamates and P-glycoprotein binding with MTX. The p38 MAPK-signaling pathway is especially associated with a pulmonary inflammatory response. These mechanisms can be applied to optimize drug treatment.
Kim
Youn-Jung
YJ
Korea Institute of Science and Technology, Cellular and Molecular Toxicology Laboratory, Cheongryang, Seoul, Korea.
Song
Mee
M
Ryu
Jae-Chun
JC
D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D004789:Enzyme Activation; D005838:Genotype; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics; D008171:Lung Diseases / Q000139:chemically induced* / Q000503:physiopathology; D008727:Methotrexate / Q000009:adverse effects* / Q000493:pharmacokinetics*; D008954:Models, Biological; D048051:p38 Mitogen-Activated Protein Kinases / Q000096:biosynthesis
D048051:p38 Mitogen-Activated Protein Kinases; D008727:Methotrexate