Variation of hepatic methotrexate 7-hydroxylase activity in animals and humans.
This study deals with individual and species variations in the converting activity of methotrexate (MTX) to 7-hydroxymethotrexate in animals and humans. When MTX 7-hydroxylase was assayed in six human liver cytosols, a 48-fold range of intersubject variation of the activity was observed. The variations were correlated to the concentrations of aldehyde oxidase activity in human subjects assayed with benzaldehyde as a substrate. Species differences of liver MTX 7-hydroxylase activity were also observed. The activity was highest in rabbits, followed by rats, hamsters, and monkeys but was undetectable in dogs. Strain differences of MTX 7-hydroxylase activity based on aldehyde oxidase activity were also observed in rats and mice. The results suggest that aldehyde oxidase functions as MTX 7-hydroxylase in livers of animals and humans, and the observed differences of MTX 7-hydroxylase activity are due to variations in the amount of aldehyde oxidase present.
Kitamura
S
S
Institute of Pharmaceutical Science, Hiroshima University School of Medicine, Japan. kitamura@pharm.hiroshima-u.ac.jp
Sugihara
K
K
Nakatani
K
K
Ohta
S
S
Ohhara
T
T
Ninomiya
S
S
Green
C E
CE
Tyson
C A
CA
D000328:Adult; D000818:Animals; D002675:Child, Preschool; D006224:Cricetinae; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D008099:Liver / Q000201:enzymology*; D008253:Macaca mulatta; D008297:Male; D008647:Mesocricetus; D008727:Methotrexate / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley
D006899:Mixed Function Oxygenases; D008727:Methotrexate