The role of small-intestinal P450 enzymes in protection against systemic exposure of orally administered benzo[a]pyrene

An intestinal epithelium-specific cytochrome P450 (P450) reductase (CPR)-knockout (IE-Cpr-null) mouse and a liver-specific CPR-knockout (liver-Cpr-null) mouse were studied for determination of the respective roles of P450 enzymes in the liver and small intestine (SI) in the clearance of orally administered benzo[a]pyrene (BaP). Pharmacokinetic analysis of blood BaP levels indicated significantly lower rates of BaP clearance in IE-Cpr-null than in wild-type (WT) mice, after oral BaP (30 mg/kg) treatment. In contrast, clearance rates for intraperitoneal BaP (45 mg/kg) were not different between IE-Cpr-null and WT mice. Furthermore, there was no significant difference between liver-Cpr-null and WT mice in BaP clearance, after either intraperitoneal or oral BaP administration. Thus, small-intestinal P450-mediated first-pass metabolism is a key determinant of the systemic bioavailability of oral BaP. In addition, we observed greater differences in the rates of clearance of oral BaP, between WT and IE-Cpr-null mice, in mice pretreated with β-naphthoflavone, to induce CYP1A1 expression, than in untreated mice. The onset of induction (at 2 h after dosing) of CYP1A1 protein expression by oral BaP administration was earlier in the SI than in extra-gut organs analyzed; for liver, lung, and kidney, induction was not observed until 4 h after dosing. Furthermore, BaP tissue burdens in SI and extra-gut organs of IE-Cpr-null mice were greater than burdens in corresponding organs of WT mice, at 6 or 24 h after BaP administration. Taken together, these findings strongly support the concept that small-intestinal CYP1A1 induction is a critical factor in protection against systemic exposure to oral BaP.