Racial and gender differences in N-acetyltransferase, xanthine oxidase, and CYP1A2 activities.
BACKGROUND
The urinary molar concentration ratios of several caffeine metabolites are indicators of specific drug metabolizing enzyme activities. The ratios of 5-acetyl-amino-6-formylamino-3-methyluracil (AFMU) to 1-methylxanthine (1X), AFMU to 1X plus 1-methyluric acid (1U), and AFMU to 1X + 1U + AFMU are indicative of N-acetyltransferase (NAT) activity; the ratios of 1U to 1X and 1U to 1U + 1X indicate xanthine oxidase activity; and the ratio of the sum of 7-demethylated metabolites (AFMU + 1X + 1U) to the precursor for all three compounds, paraxanthine (PX), is a putative indicator of CYP1A2 oxidative activity. Our objective was to discern whether there are race-, gender-, and age-related differences in these indexes of drug-metabolizing activity.


METHODS
In 342 normal healthy unrelated subjects, metabolites were measured in urine collected after administration of low-dose caffeine.


RESULTS
By two-way analysis of variance, NAT activity was higher in black subjects than in white subjects when assessed as AFMU/(1U + 1X) or as AFMU/(AFMU + 1U + 1X) (p = 0.001 and p = 0.002, respectively), but less so by use of AFMU/1X (p = 0.08). Xanthine oxidase activity, as assessed by 1U/1X or as 1U/(1U + 1X), was lower in black subjects than in white subjects (p = 0.02 and p = 0.001, respectively) and was lower in males than in females (p = 0.001 for both ratios). Females had higher AFMU/1X ratios (p = 0.03) because of higher xanthine oxidase activity. In a model in which AFMU/1X was the dependent variable and race, sex, age, and an index of xanthine oxidase (1U/1X) were independent variables, only race and 1U/1X were significant determinants of this NAT index (p = 0.003 and p < 0.001, respectively). The CYP1A2 ratio was lower in black subjects (p = 0.036) and in females (p = 0.015).


CONCLUSIONS
Racial and gender differences in xanthine oxidase activity render the AFMU/1X ratio less reliable as an assessment of NAT activity in a heterogeneous population compared with the AFMU/(1U + 1X) or AFMU/(AFMU + 1U + 1X) ratios. The observed racial and gender differences in NAT, xanthine oxidase, and CYP1A2 activities may have implications for racial and gender differences in drug effects and carcinogen biotransformation.
Relling
M V
MV
Pharmaceutical Department, St. Jude Children's Research Hospital, Memphis, TN 38105.
Lin
J S
JS
Ayers
G D
GD
Evans
W E
WE
D000293:Adolescent; D000328:Adult; D000375:Aging / Q000652:urine*; D000704:Analysis of Variance; D001191:Arylamine N-Acetyltransferase / Q000652:urine*; D002110:Caffeine / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D019388:Cytochrome P-450 CYP1A2; D003577:Cytochrome P-450 Enzyme System / Q000652:urine*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010088:Oxidoreductases / Q000652:urine*; D044469:Racial Groups; D012016:Reference Values; D012727:Sex Characteristics; D014969:Xanthine Oxidase / Q000652:urine*
D002110:Caffeine; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D019388:Cytochrome P-450 CYP1A2; D014969:Xanthine Oxidase; D001191:Arylamine N-Acetyltransferase