CYP4B1 activates 4-ipomeanol in rat lung

Area of Science:

• Toxicology
• Biochemistry
• Pharmacology

Background:

• Ipomeanol is a lung toxicant.
• Pulmonary cytochrome P450 enzymes are involved in xenobiotic metabolism.
• The specific P450 isozyme responsible for ipomeanol bioactivation in rat lungs was not clearly defined.

Purpose of the Study:

• To determine the specific cytochrome P450 (CYP) isozyme responsible for the pulmonary bioactivation of ipomeanol in rats.
• To investigate the role of CYP4B1 in ipomeanol-induced lung toxicity and covalent binding.

Main Methods:

• Rats were pretreated with p-xylene to inhibit CYP4B1, or with inducers/inhibitors of CYP1A1 and CYP2B1.
• Ipomeanol toxicity was assessed by acute lethality.
• Covalent binding of [14C]-ipomeanol to lung microsomes was measured in vitro and in vivo.
• Antibodies against CYP4B1, CYP1A1, and CYP2B1 were used to assess enzyme involvement.

Main Results:

• Pretreatment with p-xylene significantly reduced ipomeanol toxicity (by eightfold) and covalent binding of ipomeanol to lung microsomes.
• Inhibition of CYP4B1 also decreased the N-hydroxylation of 2-aminofluorene, a known CYP4B1 substrate.
• Induction of CYP1A1 or inhibition of CYP2B1 did not alter ipomeanol toxicity or binding.
• An antibody against CYP4B1 inhibited ipomeanol binding to lung microsomes in vitro.
• Administration of 2-aminofluorene, a CYP4B1 substrate, reduced ipomeanol toxicity.

Conclusions:

• Pulmonary bioactivation of ipomeanol in rats is predominantly mediated by CYP4B1.
• CYP4B1 plays a critical role in the toxic effects of ipomeanol in the rat lung.
• These findings highlight species-specific differences in ipomeanol metabolism, contrasting with findings in rabbits.