Strain differences of the ability to hydroxylate methotrexate in rats |
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| Institution: | 1. Key Laboratory of the Ministry of Education for Ecology of Rare and Endangered Species and Environmental Protection, Guangxi Normal University, Guilin 541004, Guangxi, China;2. Key Laboratory of Ministry of Education for Coastal and Wetland Ecosystems, Xiamen University, Xiamen 361102, China;3. College of Earth and Environmental Sciences, Lanzhou University, Lanzhou 730000, China;4. Institute of Environment and Ecology, School of the Environment and Safety Engineering, Jiangsu University, Zhenjiang 212013, China;1. Area of Nutrition and Food Sciences, Department of Molecular Biology and Biochemistry Engineering, Pablo de Olavide University, Carretera de Utrera Km 1, E-41013 Seville, Spain;2. Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Spain;3. Associated Researcher at Autónoma de Chile University, Av. Pedro de Valdivia 641, Santiago de Chile, Chile |
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| Abstract: | Converting activity of methotrexate (MTX) to 7-hydroxymethotrexate (7-OH-MTX) was examined using eight strains of rats. Marked variability of the activity was found in liver cytosols from the rats. The highest activity was observed with Sea:SD rats, followed by LEW/Sea and Jcl:Wistar rats. The lowest activity was observed with WKA/Sea rats. The difference in the activity between Sea:SD and WKA/Sea strains was 104-fold. The variation was correlated to the strain difference of benzaldehyde oxidase activity in the rats. The cytosolic 7-hydroxylase activities in other tissues of Sea:SD rats were much higher than those of WKA/Sea, similarly to the case in liver. The liver microsomes of Sea:SD rats exhibited no 7-hydroxylase activity toward MTX even in the presence of NADPH. The cytosolic 7-hydroxylating activity of the livers of Sea:SD rats was inhibited by menadione, β-estradiol, chlorpromazine and disulfiram, inhibitors of aldehyde oxidase, but not oxypurinol, an inhibitor of xanthine oxidase. The purified aldehyde oxidase from the livers of Sea:SD rats exhibited a significant 7-hydroxylating activity toward MTX. However, xanthine oxidase had no ability to hydroxylate MTX. These facts suggest that MTX hydroxylating activity in rats is predominantly due to aldehyde oxidase, and the strain differences are due to the variations of the flavoenzyme level. |
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