Absorption, metabolism, and excretion of di(2-ethylhexyl) phthalate by rats and mice

Abstract

There is convincing evidence in the literature that most of the adverse biological effects of phthalate diesters are actually effects of metabolites rather than of the parent compounds. If so, the dramatic species differences in endpoint metabolic profiles make it essential that metabolism of phthalates be understood in detail, including the factors that may alter the metabolism. A metabolic pathway for phthalates having saturated alkyl groups has been postulated based on identification of metabolites produced in vivo and excreted in urine. The first few steps in the postulated pathway have been confirmed in vitro using enzymatically active preparations from rats and mice; some details of the nature of these early steps have been learned. Although some information concerning later steps is available, much remains to be learned in this area. Species differences are postulated to involve kinetics of several biochemical and physiological events acting in concert or competition. Among these interacting factors are competition of at least three enzymes for phthalate monoesters as substrate, relative kidney clearance rates for different metabolites, relative Km values of oxidative enzymes for the same precursors in different species, and relative equilibria between glucuronide formation and hydrolysis. Essential information that must be obtained in the future includes which metabolites play a causal role in which biological effects, and what factors (age, diet, state of health, etc.) can modify the metabolism of phthalate esters and in what way.