In vitro conjugation of benzene metabolites by human liver: potential influence of interindividual variability on benzene toxicity.
In addition to industrial sources, benzene is present in the environment as a component of cigarette smoke and automobile emissions. Toxicity of benzene most likely results from oxidative metabolism of benzene to reactive products. However, susceptibility to these toxic effects may be related to a balance between activation (phase I) and detoxication (phase II) reactions. In the present study, we have estimated kinetic parameters of the two major detoxication reactions for benzene metabolites--phenol sulfation and hydroquinone glucuronidation--in liver subcellular fractions from 10 humans, and single samples from mice and rats. The extent of oxidative metabolism of benzene by these liver samples has been reported previously. Here, initial rates of phenol sulfation varied 3-fold (range 0.309-0.919 nmol/mg protein/min) among human samples. Measured rates were faster in rats (1.195 nmol/mg protein/min) than in mice (0.458 nmol/mg protein/min). Initial rates of hydroquinone glucuronidation by human samples also varied 3-fold (range 0.101-0.281 nmol/mg protein/min). Hydroquinone glucuronidation was more rapid by mouse microsomes (0.218 nmol/mg protein/min) than by rat microsomes (0.077 nmol/mg protein/min). To integrate interindividual differences in various enzyme activities, a physiological compartmental model was developed that incorporates rates of both conjugation reactions and oxidation reactions. Model equations were solved for steady-state concentrations of phenol and hydroquinone attained in human, mouse and rat blood during continuous exposure to benzene (0.01 microM in blood). Among the 10 human subjects, steady-state concentrations of phenol varied 6-fold (range 0.38-2.17 nM) and steady-state concentrations of hydroquinone varied 5-fold (range 6.66-31.44 nM). Predicted steady-state concentrations of phenol were higher in mice compared with rats (2.28 and 0.83 nM respectively). Likewise, higher steady-state concentrations of hydroquinone were predicted in mice than in rats (42.44 and 17.99 nM respectively). Predicted steady-state concentrations of phenol and hydroquinone in mice were higher than predictions for the 10 human subjects, whereas predicted concentrations for rats fell among the human values. As such, our results underscore the importance of considering the balance between activation and detoxication reactions in the elimination of toxicants. Model simulations suggest that both phase I and phase II pathways influence the relative risk from exposure to benzene.
Seaton
M J
MJ
Chemical Industry Institute of Toxicology, Research Triangle Park, NC 27709, USA.
Schlosser
P
P
Medinsky
M A
MA
D000293:Adolescent; D000328:Adult; D000818:Animals; D001554:Benzene / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity*; D001711:Biotransformation; D001825:Body Fluid Compartments; D002675:Child, Preschool; D005260:Female; D005965:Glucuronates / Q000378:metabolism; D006801:Humans; D006873:Hydroquinones / Q000378:metabolism / Q000493:pharmacokinetics; D008658:Inactivation, Metabolic; D007206:Individuality; D007700:Kinetics; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008875:Middle Aged; D009153:Mutagens / Q000378:metabolism / Q000493:pharmacokinetics; D019800:Phenol; D010636:Phenols / Q000378:metabolism / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley
D005965:Glucuronates; D006873:Hydroquinones; D009153:Mutagens; D010636:Phenols; D019800:Phenol; D001554:Benzene; C031927:hydroquinone