The emerging brominated
flame retardant, 1,2-dibromo-4-(1,2-dibromoethyl)cyclohexane
(TBECH), has recently attracted strong interest due to its extensive
detection in the environment and potential toxicological effects on
humans. Previous in vitro experiments have shown
that the technical mixture of TBECH and the pure β-isomer (β-TBECH)
can be metabolized by cytochrome P450 enzymes (CYPs) into multiple
metabolites, but the specific CYP isoforms involved in TBECH metabolism
and the relevant metabolic regioselectivity remain unknown. Here,
we, for the first time, investigated the binding patterns and affinities
of β-TBECH in human CYPs 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1,
and 3A4, through molecular dynamics (MD) simulations. The binding
affinities of β-TBECH in CYPs, which are estimated by the calculated
binding free energies, follow the order of 2A6 > 2C9 > 2B6 >
2E1 >
3A4 ≈ 2C19 ≈ 1A2 > 2D6. Although all CYPs are important
β-TBECH receptors, only 2A6, 2C19, 2E1, and 3A4 are responsible
for metabolizing β-TBECH. Specially, 2A6 and 2E1 may selectively
hydroxylate the C1 and C7 sites of β-TBECH,
while 2C19 and 3A4 show metabolic preference for C7- and
C8-hydroxylations, respectively. The three hydroxylation
routes proposed by the further density functional theory (DFT) calculations
generate C1-, C7-, and C8-hydroxylated
metabolites, while the latter two may further undergo debromination
to yield the respective ketone and aldehyde as additional metabolites.
The results provide meaningful insight into the binding and metabolism
of β-TBECH by human CYPs, which is helpful for understanding
the metabolic fate and toxicity mechanism of this chemical.