Choline deficiency and treatment with
methotrexate (MTX) both are associated with fatty infiltration of the liver.
Choline,
methionine, and
folate metabolism are interrelated and converge at the regeneration of
methionine from
homocysteine. MTX perturbs
folate metabolism, and it is possible that it also influences
choline metabolism. We fed rats a
choline deficient diet for 2 weeks and/or treated them with
methotrexate (MTX; 0.1 mg/kg daily).
Choline deficiency lowered hepatic concentrations of
choline (to 43% control),
phosphocholine (
PCho; to 18% control), glycerophosphocholine (GroPCho; to 46% control),
betaine (to 30% control),
phosphatidylcholine (PtdCho; to 62% control),
methionine (to 80% control), and
S-adenosylmethionine (
AdoMet; to 57% control), while
S-adenosylhomocysteine (AdoHcy) and
triacylglycerol concentrations increased (to 126% and 319% control, respectively). MTX treatment alone lowered hepatic concentrations of
PCho (to 48% control), GroPCho (to 69% control),
betaine (to 55% control), and
AdoMet (to 75% control). The addition of MTX treatment to
choline deficiency resulted in a larger decrease in
AdoMet concentrations (to 75% control) and larger increases in AdoHcy and
triacylglycerol concentrations (to 150% and 500% control, respectively) than was observed in
choline deficiency alone. Livers from MTX-treated animals used radiolabeled
choline to make the same metabolites as did livers from controls (most of the label was converted to
PCho and
betaine). In
choline deficient animals, most of the labeled
choline was converted to PtdCho. Therefore, MTX depleted hepatic
PCho, GroPCho, and
betaine by a mechanism that was different from that of
choline deficiency. MTX increased the extent of fatty infiltration of the liver in
choline deficient rats, and
choline deficiency and MTX treatment damaged hepatocytes as measured by leakage of
alanine aminotransferase activity. Our data are consistent with the hypothesis that the fatty infiltration of the liver associated with MTX treatment occurs because of a disturbance in
choline metabolism.