Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous and often carcinogenic
contaminants released into the environment during natural and anthropogenic combustion
processes. Benzo[a]pyrene (B[a]P) is the prototypical carcinogenic PAH, and
dibenzo[def,p]chrysene (DBC) is a less prevalent, but highly potent transplacental
carcinogenic PAH. Both are metabolically activated by isoforms of the cytochrome P450
enzyme superfamily to form reactive carcinogenic and cytotoxic metabolites. Metabolism of
B[a]P and DBC was studied in hepatic microsomes of male Sprague-Dawley rats, naïve
and pregnant female B6129SF1/J mice, and female humans, corresponding to available
pharmacokinetic data. Michaelis–Menten saturation kinetic parameters including
maximum rates of metabolism (VMAX, nmol/min/mg microsomal
protein), affinity constants (KM, μM), and rates of
intrinsic clearance (CLINT, ml/min/kg body weight) were
calculated from substrate depletion data. CLINT was also
estimated from substrate depletion data using the alternative in vitro
half-life method. VMAX and CLINT
were higher for B[a]P than DBC, regardless of species. Clearance for both B[a]P and DBC
was highest in naïve female mice and lowest in female humans. Clearance rates of
B[a]P and DBC in male rat were more similar to female human than to female mice. Clearance
of DBC in liver microsomes from pregnant mice was reduced compared to naïve mice,
consistent with reduced active P450 protein levels and elevated tissue concentrations and
residence times for DBC observed in previous in vivo pharmacokinetic
studies. These findings suggest that rats are a more appropriate model organism for human
PAH metabolism, and that pregnancy's effects on metabolism should be further explored.
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