COMPARISON AND IN-VIVO RELEVANCE OF 2 DIFFERENT IN-VITRO HEAD SPACE METABOLIC SYSTEMS - LIVER S9 AND LIVER SLICES

In vitro systems of high biological organization, e.g. containing inta ct hepatocytes, have been considered as more reliable for metabolic st udies and in vivo predictions of toxicokinetics than subcellular syste ms. For this reason, the kinetics and metabolism of low-molecular-weig ht volatile chemicals, i.e. head space elimination of substrate and fo rmation of metabolites, were compared in liver S9 and in liver slices. Two substrates, toluene and n-hexane, were used as they represent dif ferences in metabolic pathways and physical-chemical properties. The t wo systems responded similarly to diethyldithiocarbamate inhibition an d acetone inhibition/induction of cytochrome P-450 mediated metabolism . In contrast to liver S9, liver slices did not respond adequately to phenobarbital induction raising the question of substrate availability for P-450 enzymes in liver slices. Liver slices appeared to be superi or to liver S9 when specific metabolic pathways involving phase II enz ymes were investigated. However, liver S9 seemed to be at least as goo d as liver slices for estimation of total metabolic rare constants (K- m, V-max) as a basis for in vivo predictions. As the head space liver S9 system is faster and easier to operate than liver slices, it is a p romising screening tool for the metabolism of volatile compounds and m etabolic interactions.