Theophylline N-demethylations as probes for P4501A2 and P4501A1. Drug Metab. Dispos

Polycyclic aromatic hydrocarbons present in cigarette smoke induce cytochromes P4501A1 and P4501A2. These isozymes are of toxico-logical importance because they convert several environmental pol-lutants to reactive intermediates that form covalent adducts with cellular DNA resufting in mutations and/or malignant transformations. The aim of our research was to investigate whether theophylline metabolites could be used as probes for P4501A1 and P4501A2. It is known that at least two human P450 isozymes are involved in theophylline metabolism. The N-demethylations of theophylline to 3-methylxanthine (3-MX) and 1-methylxanthine (1-MX) appear to be mediated by P4501A1 and/or P4501*2 and the 8-hydroxylation by different isozymes. Theophylline metabolism was measured in liver microsomes from control, benzo(a)pyrene (BP)-, and isosafrole (ISO)-induced rats. Theophylline was also incubated in microsomes prepared from cells expressing high levels of human P4501A1 an