Expression of deoxynucleoside kinases and 5'-nucleotidases in mouse tissues: implications for mitochondrial toxicity.
Anti-HIV nucleoside therapy can result in mitochondrial toxicity affecting muscles, peripheral nerves, pancreas and adipose tissue. The cytosolic deoxycytidine kinase (dCK; EC 2.7.1.74) and thymidine kinase (TK1; EC 2.7.1.21), the mitochondrial thymidine kinase (TK2) and deoxyguanosine kinase (dGK; EC 2.7.1.113) as well as 5'-deoxynucleotidases (5'-dNT; EC 3.1.3.5) are enzymes that control rate-limiting steps in formation of intracellular and intra-mitochondrial nucleotides. The mRNA levels and activities of these enzymes were determined in mouse tissues, using real-time PCR and selective enzyme assays. The expression of mRNA for all these enzymes and the mitochondrial deoxynucleotide carrier was detected in all tissues with a 5-10-fold variation. TK1 activities were only clearly detected in spleen and testis, while TK2, dGK and dCK activities were found in all tissues. dGK activities were higher than any other dNK in all tissues, except spleen and testis. In skeletal muscle dGK activity was 5-fold lower, TK2 and dCK levels were 10-fold lower as compared with other tissues. The variation in 5'-dNT activities was about eight-fold with the highest levels in brain and lowest in brown fat. Thus, the salvage of deoxynucleosides in muscles is 5-10-fold lower as compared to other non-proliferating tissues and 100-fold lower compared to spleen. These results may help to explain tissue specific toxicity observed with nucleoside analogs used in HIV treatment as well as symptoms in inherited mitochondrial TK2 deficiencies.
Rylova
Svetlana N
SN
Department of Anatomy, Physiology and Biochemistry, Section of Veterinary Medical Biochemistry, SLU, The Biomedical Center, P.O. Box 575, SE-751 23 Uppsala, Sweden.
Mirzaee
Saeedeh
S
Albertioni
Freidoun
F
Eriksson
Staffan
S
D015720:5'-Nucleotidase / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D002001:Adipose Tissue, Brown / Q000737:chemistry / Q000201:enzymology; D000818:Animals; D015870:Gene Expression; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D018482:Muscle, Skeletal / Q000737:chemistry / Q000201:enzymology; D009705:Nucleosides / Q000633:toxicity; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000633:toxicity; D013154:Spleen / Q000737:chemistry / Q000201:enzymology; D013737:Testis / Q000737:chemistry / Q000201:enzymology
D009705:Nucleosides; D012333:RNA, Messenger; D018894:Reverse Transcriptase Inhibitors; D017853:Phosphotransferases (Alcohol Group Acceptor); C020018:deoxyribonucleoside kinases; D015720:5'-Nucleotidase