Effects of chronic exposure to low-level cadmium on renal tubular function and CYP2A6-mediated coumarin metabolism in healthy human subjects.
Relationships between cadmium (Cd) body burden, kidney function and coumarin metabolism were investigated using two groups of 197 and 200 healthy Thais with men and women in nearly equal numbers. A mean age of one group was 30.5 years and it was 39.3 years for the other group. Of 397, 20 subjects (5%) excreted urine Cd between 1.4 microg/g and 3.8 microg/g creatinine and these subjects faced 10-15% increase in the probability of having abnormal urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG-uria). The prevalence of NAG-uria varied with Cd body burden in a dose-dependent manner (chi2 = 22, P < 0.008). Also NAG-nuria was one of the three kidney effect markers tested that showed the greatest strength of correlation with urine Cd in both men and women (r = 0.48, P < 0.001). In addition, urine Cd excretion of men and women showed a positive correlation (r = 0.46 to 0.54, P < 0.001) with urine 7-hydroxycoumarin (7-OHC) excretion which was used as a marker of liver cytochrome P450 2A6 (CYP2A6) enzyme activity. Urinary Cd excretion accounted for 25% of the total variation in urine 7-OHC excretion (P < 0.001). These data suggest that Cd may increase the expression of CYP2A6 in liver, resulting in enhanced coumarin metabolism in subjects with high Cd body burden.
Satarug
Soisungwan
S
National Research Centre for Environmental Toxicology (EnTox), The University of Queensland, 39 Kessels Road, Coopers Plains, Brisbane, Qld. 4108, Australia. s.satarug@uq.edu.au
Nishijo
Muneko
M
Ujjin
Pailin
P
Vanavanitkun
Yuvaree
Y
Baker
Jason R
JR
Moore
Michael R
MR
D000328:Adult; D000925:Anticoagulants / Q000378:metabolism*; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D002104:Cadmium / Q000652:urine; D002105:Cadmium Poisoning / Q000201:enzymology* / Q000473:pathology* / Q000652:urine; D003374:Coumarins / Q000378:metabolism*; D065637:Cytochrome P-450 CYP2A6; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007684:Kidney Tubules / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D014468:Umbelliferones / Q000378:metabolism
D000925:Anticoagulants; D003374:Coumarins; D014468:Umbelliferones; D002104:Cadmium; C031477:7-hydroxycoumarin; C030123:coumarin; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6