INDUCTION OF ARYL HYDROCARBON HYDROXYLASE (AHH) FORMS OF CYTOCHROME P-450 CAN BE MONITORED BY CAFFEINE URINARY METABOLITE RATIOS

Abstract

A major biological effect of toxic environmental chemicals such as the dioxins and polyhalogenated biphenyls is induction of specific forms of cytochrome P-450 (AHH). There is a need for non-invasive approaches to monitoring effects of chemical exposures suitable for large population studies. Caffeine is metabolized in part by AHH. We have studied urinary metabolite products of caffeine as a means of determining AHH activity following ingestion of small doses of caffeine in beverages. In a study of 15 adult subjects, a good correlation was found between systemic caffeine clearance and urinary molar ratios of paraxanthine-7-demethylation products relative to a paraxanthine-8-hydroxylation product (r=0.91, p<0.001). In a larger population study, we found: 1. no gender differences in adults or prepubertal children; 2. no differences between Orientals (n=26) and Caucasians (n=42); 3. prepubertal children (n=21) showed a higher (p<0.001) mean metabolite ratio than adults (n=61); 4. oral contraceptive users (n=9) had lower (p<0.05) ratio than women not using oral contraceptives (n=30); 5. smokers (n=26) had a higher (p<0.001) ratio than non-smokers (n=61). In a separate study, an good correlation was found between the urinary metabolite ratio and caffeine clearance as estimated by the ¹³C-caffeine breath test. Use of caffeine metabolite ratios in urine following ingestion of the compound in coffee or cola beverages provides a safe, inexpensive way of monitoring populations for induction of AHH, and for examining the effects of exposure to environmental chemicals early in life on the ontogeny and regulatbn of this important class of oxidative drug metabolizing enzymes.

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