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In vivo inhibition of human CYP1A2 activity by oltipraz
G G Sofowora1, E F Choo, G Mayo
1Department of Pharmacology, Vanderbilt University, Nashville, TN 37232-6600, USA. grant.wilkinson@mcmail.vanderbilt.edu
Purpose:
Oltipraz is currently undergoing clinical evaluation as a cancer chemopreventive agent, especially with respect to aflatoxin-associated hepatocarcinogenesis. The agent's ability to induce phase II xenobiotic enzymes that detoxify the ultimate carcinogen formed in vivo is thought to be an important mechanism by which disease risk may be attenuated. However, an additional mechanism could be a reduction in the activation of environmental procarcinogens by certain cytochrome P450 (CYP) isoforms. This hypothesis was tested with respect to CYP1A2, by using the clearance of caffeine by N-demethylation as a phenotypic trait measurement of the isoform's catalytic activity.
Methods:
Subjects received a single oral dose of caffeine (200 mg) on five separate occasions: on the day prior to oltipraz administration (day 0), 2 h after the first (day 1) of eight daily oral doses of oltipraz (125 mg) and 2 h after the last dose (day 8). In addition, CYP1A2 activity was also measured 2 and 14 days (days 10 and 22, respectively) after discontinuation of oltipraz administration. Plasma concentrations of caffeine and its N-demethylated metabolite, paraxanthine, over 24 h after drug administration, were determined by HPLC.
Results:
A single 125-mg dose of oltipraz markedly reduced CYP1A2 activity by 75 +/- 13% in nine healthy subjects, resulting in a higher caffeine plasma level and prolongation of the in vivo probe's elimination half-life. Daily administration of 125 mg oltipraz for 8 days resulted in further inhibition so that only 19 +/- 13% of the original baseline level of activity was present. However, 2 days after discontinuation of oltipraz treatment, CYP1A2 activity had returned to 66 +/- 33% of its original level and complete recovery was achieved within 14 days of the chemopreventive agent being stopped.
Conclusions:
These results demonstrate that oltipraz is a potent, in vivo inhibitor of CYP1A2 in humans and, because this isoform is importantly involved in procarcinogen activation, they also indicate that such inhibition probably contributes to oltipraz's cancer-chemopreventive effect. In addition, the findings also suggest the likelihood of significant drug interactions between oltipraz and drugs whose metabolism is mediated by CYP1A2.
Insights
Oltipraz significantly inhibits CYP1A2 activity in humans, a key enzyme in procarcinogen activation. This potent inhibition likely contributes to oltipraz's cancer chemopreventive effects and may lead to drug interactions.
Area of Science:
- Pharmacology
- Cancer Chemoprevention
- Drug Metabolism
Background:
- Oltipraz is evaluated for cancer chemoprevention, particularly for aflatoxin-induced liver cancer.
- Its mechanism may involve inducing phase II enzymes or reducing procarcinogen activation by cytochrome P450 (CYP) isoforms.
- This study investigates oltipraz's effect on CYP1A2, a crucial enzyme in procarcinogen activation.
Purpose of the Study:
- To test the hypothesis that oltipraz reduces procarcinogen activation by inhibiting CYP1A2.
- To measure CYP1A2 activity in vivo using caffeine N-demethylation as a phenotypic marker.
Main Methods:
- Healthy subjects received oral caffeine (200 mg) on five occasions relative to oltipraz administration (125 mg daily for 8 days).
- CYP1A2 activity was assessed by measuring plasma concentrations of caffeine and its metabolite, paraxanthine, over 24 hours.
- Measurements were taken before, during, and after oltipraz treatment to evaluate its inhibitory effects and recovery.
Main Results:
- A single 125-mg dose of oltipraz reduced CYP1A2 activity by 75%, increasing caffeine levels and half-life.
- After 8 days of daily dosing, CYP1A2 activity was inhibited to 19% of baseline.
- CYP1A2 activity recovered to 66% within 2 days and fully within 14 days after discontinuing oltipraz.
Conclusions:
- Oltipraz is a potent in vivo inhibitor of human CYP1A2.
- This inhibition likely contributes to oltipraz's cancer chemopreventive properties by reducing procarcinogen activation.
- Significant drug interactions are possible between oltipraz and medications metabolized by CYP1A2.