DFT investigation on the metabolic mechanisms of theophylline by cytochrome P450 monooxygenase.

Theophylline, one of the most commonly used bronchodilators and respiratory stimulators for the treatment of acute and chronic asthmatic conditions, can cause permanent neurological damage through chronic or excessive ingestion. In this work, DFT calculation was performed to identify the metabolic mechanisms of theophylline by cytochrome P450 (CYP450) monooxygenase. Two main metabolic pathways were investigated, namely, N- (path A) and N- (path B) demethylations, which proceeded through N-methyl hydroxylation followed by the decomposition of the generated carbinolamine species. N-methyl hydroxylation involved a hydrogen atom transfer (HAT) mechanism, which can be generalized as the N-demethylation mechanism of xanthine derivatives. The energy gap between the low-spin double state (LS) and the high-spin quartet state (HS) was low (<1 kcal mol), indicating a two-state reactivity (TSR) mechanism. The generated carbinolamine species preferred to decompose through the adjacent heteroatom (O for path A and O for path B) mediated mechanism. Path B was kinetically more feasible than path A attributed to its relatively lower activation energy. 1-Methylxanthine therefore was the energetically favorable metabolite of theophylline. The observations obtained in the work were in agreement with the experimental observation, which can offer important implications for further pharmacological and clinic studies.