Chloride concentrations in human hepatic cytosol and mitochondria are a function of age.
We recently reported that, in a concentration-dependent manner, chloride protects hepatic glutathione transferase zeta 1 from inactivation by dichloroacetate, an investigational drug used in treating various acquired and congenital metabolic diseases. Despite the importance of chloride ions in normal physiology, and decades of study of chloride transport across membranes, the literature lacks information on chloride concentrations in animal tissues other than blood. In this study we measured chloride concentrations in human liver samples from male and female donors aged 1 day to 84 years (n = 97). Because glutathione transferase zeta 1 is present in cytosol and, to a lesser extent, in mitochondria, we measured chloride in these fractions by high-performance liquid chromatography analysis following conversion of the free chloride to pentafluorobenzylchloride. We found that chloride concentration decreased with age in hepatic cytosol but increased in liver mitochondria. In addition, chloride concentrations in cytosol, (105.2 ± 62.4 mM; range: 24.7-365.7 mM) were strikingly higher than those in mitochondria (4.2 ± 3.8 mM; range 0.9-22.2 mM). These results suggest a possible explanation for clinical observations seen in patients treated with dichloroacetate, whereby children metabolize the drug more rapidly than adults following repeated doses, and also provide information that may influence our understanding of normal liver physiology.
Department of Medicinal Chemistry, University of Florida, Gainesville, FL 32610-0485, United States.
Stephan C
SC
Jahn
Department of Medicinal Chemistry, University of Florida, Gainesville, FL 32610-0485, United States.
Laura
L
Rowland-Faux
Department of Medicine, University of Florida, Gainesville, FL 32610-0226, United States; Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL 32610, United States.
Peter W
PW
Stacpoole
Department of Medicinal Chemistry, University of Florida, Gainesville, FL 32610-0485, United States. Electronic address: mojames@ufl.edu.
Margaret O
MO
James
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D002712:Chlorides / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003600:Cytosol / Q000378:metabolism; D003999:Dichloroacetic Acid / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D017136:Ion Transport; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008659:Metabolic Diseases / Q000188:drug therapy / Q000378:metabolism; D008875:Middle Aged; D008930:Mitochondria, Liver / Q000378:metabolism; D055815:Young Adult
D002712:Chlorides; D004791:Enzyme Inhibitors; D003999:Dichloroacetic Acid; C407705:GSTZ1 protein, human; D005982:Glutathione Transferase
Chloride; Cytosol; Dichloroacetate; GSTZ1; Liver; Mitochondria