CYP2D6, GST-M1 and GST-T1 enzymes: expression in parathyroid gland and association with the parathyroid hormone concentration during early renal replacement therapy.
OBJECTIVE
The purpose of this research was to characterize CYP2D6, GST-M1 and GST-T1 enzyme expression in human parathyroid tissue, and to determine whether or not there is any association between deficiencies in these enzymes and serum parathyroid hormone concentrations in patients with end-stage renal disease.


METHODS
Surgical human parathyroid tissue was obtained and evaluated by immunohistochemistry for cellular localization of CYP2D6, GST-M1 and GST-T1 and colocalization of CYP2D6 with parathyroid hormone. Blood samples were collected from 328 Caucasian patients with end-stage renal disease for genetic testing of CYP2D6*3, *4, *5, *6, *7 and GST-M1*0 and GST-T1*0 alleles. Clinical chemistry data and serum intact parathyroid hormone (iPTH) concentrations were obtained from patient medical records. In 277 of the patients, the same laboratory performed all clinical tests.


RESULTS
CYP2D6, GST-M1 and GST-T1 were present in human parathyroid tissue. CYP2D6 was colocalized with parathyroid hormone in parathyroid chief cells. Within the end-stage renal disease population, a nonfunctional CYP2D6 genotype was present in 18.2%[95% confidence interval (CI) 8.0, 28.4] of patients in the 1st iPTH concentration quintile (iPTH < 64 pg x mL(-1)), in 0% (95% CI 0, 7.5) of those in the 2nd quintile, in 1.8% (95% CI 0, 9.3) of those in the 3rd quintile, in 9.1% (95% CI 1.5, 16.7) of those in the 4th quintile, and in 16.7% (95% CI 6.8, 26.5) of those in the 5th quintile (iPTH > 347 pg x mL(-1)) (P = 0.001). Out of 12 CYP2D6-deficient females, seven were in the 1st iPTH concentration quintile and the remaining five were in the 5th quintile. Patients deficient in the GST-M1 and GST-T1 enzymes displayed a far more uniform frequency distribution relative to serum iPTH concentrations.


CONCLUSIONS
The presence of CYP2D6, GST-M1 and GST-T1 in parathyroid cells was observed. An association is reported between a lack of CYP2D6 and iPTH concentrations in newly diagnosed end-stage renal disease patients. Gender and concomitant deficiency in GST-M1 and/or GST-T1 appear to define this association further. It remains to be established whether these associations reflect a cause-effect relationship between deficient expression of metabolizing enzymes and severity of secondary manifestation of renal failure.
Yan
Feng-Xiang
FX
Division of Nephrology, Bone and Mineral Metabolism, College of Medicine, University of Kentucky, Lexington, KY, USA.
Langub
M Chris
MC
Ihnen
Mark A
MA
Hornung
Carlton
C
Juronen
Erkki
E
Rayens
Mary K
MK
Cai
Wei-Min
WM
Wedlund
Peter J
PJ
Fanti
Paolo
P
D000293:Adolescent; D000328:Adult; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007676:Kidney Failure, Chronic / Q000378:metabolism / Q000628:therapy; D008297:Male; D008875:Middle Aged; D010280:Parathyroid Glands / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000235:genetics / Q000378:metabolism*; D011110:Polymorphism, Genetic / Q000235:genetics; D017582:Renal Replacement Therapy
D019389:Cytochrome P-450 CYP2D6; D005982:Glutathione Transferase; D010281:Parathyroid Hormone; C413545:glutathione S-transferase T1