Lack of effect of growth hormone replacement therapy on CYP1A2 and xanthine oxidase activities in growth hormone-deficient children.
OBJECTIVE
The recombinant human growth hormone (rhGH) is being increasingly used for a number of metabolic alterations. GH is the main regulator of several hepatic drug metabolizing enzymes in rodents. In addition, GH could play a major role in defining the interface between pharmacogenetics and development. However, little is known about the effect of GH on the activity of hepatic enzymes in children. The aim of this study was to determine the effect of rhGH replacement therapy for 4 weeks on CYP1A2 and xanthine oxidase (XO) activities in children.


METHODS
We used caffeine as a probe drug to assess the enzyme activities at two points in time: before starting GH treatment (day 0) and after 4 weeks on rhGH therapy (day A). A total of 31 GH-deficient children (age range: 4.1-13.1 years, mean age: 9.88+/-2.89 years) participated. Urinary concentrations of caffeine and metabolites were determined by high-performance liquid chromatography (HPLC) to calculate the metabolite ratios: (AFMU+1X+1U)/17U for CYP1A2 and 1U/(1X+1U) for XO.


RESULTS
Four weeks of GH substitution did not importantly alter the markers of the enzyme activities measured in this study. Median values and 95% confidence intervals (CI) at baseline were 5.17 (3.87-5.59) for the CYP1A2 ratio and 0.62 (0.56-0.65) for the XO ratio. These values, after treatment, were 4.57 (3.90-5.97) for the CYP1A2 marker and 0.62 (0.59-0.67) for the XO ratio. Data comparison between periods showed lack of statistically significant differences (P>0.05). The relative changes measured by the ratios of medians and 90% CI were 1.14 (0.90-1.31) and 0.99 (0.94-1.06) for CYP1A2 and XO, respectively.


CONCLUSIONS
The absence of significant changes in the markers of enzyme activities CYP1A2 and XO suggests that rhGH replacement therapy of GH-deficient children for 4 weeks could not noticeably modify the efficacy or toxicity of substrates of these metabolic enzymes.
Mayayo-Sinués
Esteban
E
Department of Pharmacology, Medicine School, University of Zaragoza, Domingo Miral s/n, 50009, Zaragoza, Spain.
Fanlo
Ana
A
Sinués
Blanca
B
Mayayo
Esteban
E
Labarta
Jose I
JI
García de Jalón
Angel
A
Ferrández-Longás
Angel
A
D000293:Adolescent; D015415:Biomarkers / Q000378:metabolism; D002110:Caffeine; D002648:Child; D002675:Child, Preschool; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D005260:Female; D020249:Hormone Replacement Therapy; D019382:Human Growth Hormone / Q000008:administration & dosage / Q000172:deficiency* / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D014969:Xanthine Oxidase / Q000378:metabolism*
D015415:Biomarkers; D011994:Recombinant Proteins; D019382:Human Growth Hormone; D002110:Caffeine; D019388:Cytochrome P-450 CYP1A2; D014969:Xanthine Oxidase