Phenylalanine-induced leucopenia in genetic and dichloroacetic acid generated deficiency of glutathione transferase Zeta.
Glutathione transferase Zeta (GSTZ1-1) is identical to maleylacetoacetate isomerase and catalyses a significant step in the catabolism of phenylalanine and tyrosine. Exposure of GSTZ1-1 deficient mice to high dietary phenylalanine causes a rapid loss of circulating white blood cells (WBCs). The loss was significant (P<0.05) after 2 days and total WBCs were reduced by 60% after 6 days. The rapid loss of WBCs was attributed to the accumulation of the catabolic intermediates maleylacetoacetate or maleylacetone (MA) in the circulation. Serum from GSTZ1-1 deficient mice treated with phenylalanine was cytotoxic to splenocytes from normal BALB/c mice and direct incubation of normal splenocytes with MA caused a rapid loss of viability. Dichloroacetic acid (DCA) has been used therapeutically to treat lactic acidosis and is potentially of use in cancer chemotherapy. Since DCA can inactivate GSTZ1-1 there is a possibility that long-term treatment of patients with DCA could cause GSTZ1-1 deficiency and susceptibility to oxidative stress and phenylalanine/tyrosine-induced WBC loss. However, although we found that DCA at 200mg/(kg day) causes a severe loss of hepatic GSTZ1-1 activity in BALB/c mice, it did not induce WBC cytotoxicity when combined with high dietary phenylalanine.
John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia.
Angelo
A
Theodoratos
Wen Juan
WJ
Tu
Jean
J
Cappello
Anneke C
AC
Blackburn
Klaus
K
Matthaei
Philip G
PG
Board
D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D003470:Culture Media; D003999:Dichloroacetic Acid / Q000009:adverse effects* / Q000494:pharmacology; D004906:Erythrocyte Count; D005978:Glutathione / Q000097:blood; D005982:Glutathione Transferase / Q000172:deficiency* / Q000235:genetics; D007958:Leukocyte Count; D007962:Leukocytes / Q000166:cytology; D007970:Leukopenia / Q000097:blood / Q000139:chemically induced* / Q000235:genetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010649:Phenylalanine / Q000009:adverse effects* / Q000097:blood / Q000494:pharmacology; D013154:Spleen / Q000166:cytology
D003470:Culture Media; D010649:Phenylalanine; D003999:Dichloroacetic Acid; C498694:Gstz1 protein, mouse; D005982:Glutathione Transferase; D005978:Glutathione