Elevated homocysteine, glutathione and cysteinylglycine concentrations in patients homozygous for the Chuvash polycythemia VHL mutation.
In Chuvash polycythemia, homozygous von Hippel-Lindau (VHL) 598C>T leads to increased hypoxia inducible factor-1alpha and 2alpha, thromboses and lower systemic blood pressures. Circulating homocysteine, glutathione, gamma-glutamyltransferase and cysteinylglycine concentrations were higher in 34 VHL598C>T homozygotes than in 37 normal controls and cysteine was lower. Multivariate analysis showed elevated homocysteine independently associated with higher mean systemic blood pressures and elevated glutathione was associated with lower pressures to a similar degree. Among VHL598C>T homozygotes, homocysteine was elevated with low and normal folate concentrations, consistent with a possible defect in the remethylation pathway. The elevated glutathione and gamma-glutamyltransferase levels correlated positively with cysteinylglycine, consistent with possible upregulation of a glutathione synthetic enzyme and gamma-glutamyltransferase. Cysteinylglycine correlated inversely with cysteine, consistent with possible reduced cysteinyldipeptidase activity. We conclude that up-regulated hypoxia-sensing may influence multiple steps in thiol metabolism. The effects of the resultant elevated levels of homocysteine and glutathione on systemic blood pressure may largely balance each other out.
Sergueeva
Adelina I
AI
Cheboksary Children's Hospital, Cheboksary, Russia.
Miasnikova
Galina Y
GY
Okhotin
Daniel J
DJ
Levina
Alla A
AA
Debebe
Zufan
Z
Ammosova
Tatiana
T
Niu
Xiaomei
X
Romanova
Elena A
EA
Nekhai
Sergei
S
DiBello
Patricia M
PM
Jacobsen
Donald W
DW
Prchal
Josef T
JT
Gordeuk
Victor R
VR
D001794:Blood Pressure / Q000235:genetics; D004151:Dipeptides / Q000097:blood*; D005260:Female; D030342:Genetic Diseases, Inborn / Q000097:blood* / Q000378:metabolism; D005978:Glutathione / Q000097:blood*; D006710:Homocysteine / Q000097:blood*; D006720:Homozygote; D006801:Humans; D008297:Male; D017354:Point Mutation; D011086:Polycythemia / Q000097:blood* / Q000235:genetics; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics* / Q000378:metabolism; D005723:gamma-Glutamyltransferase / Q000378:metabolism
D004151:Dipeptides; D006710:Homocysteine; C028505:cysteinylglycine; D005723:gamma-Glutamyltransferase; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D005978:Glutathione