Metabolic capacity and interindividual variation in toxicokinetics of styrene in volunteers

Abstract

<jats:p> The aim of the present study was to assess the interindividual variation in styrene toxicokinetics and to correlate this variation with the individual metabolic capacity for cytochromeP450 (CYP), CYP2E1, CYP1A2 and CYP2D6. Twenty male volunteers were exposed on separate occasions to 104±3 and 360 ± 20 mg/m<jats:sup>3</jats:sup> of styrene for 1 h while performing 50 W physical exercise on a bicycle ergometer. Styrene concentrations in blood and mandelic (MA) and phenylglyoxylic acid (PGA) in urine were measured. The metabolic capacity was assessed by phenotyping with chlorzoxazone (CYP2El), caffeine (CYP1A2), dextromethorphan (CYP2D6) and antipyrine (CYP450). In addition, for the main styrene-metabolising enzyme, CYP2E1, genotyping for the genetic polymorphisms of the gene was performed. The average pulmonary retention of styrene was 62 ± 7% at both exposure concentrations, and the 24-h excretion of MA and PGA accounted for 58% of the dose at both concentrations. The interindividual variation in styrene kinetics ranged from 19% for the terminal half-life (t<jats:sub>1/2,β</jats:sub>) of styrene to 41% for the cumulative excretion of MA and PGA. However, no correlation between the apparent blood clearance of styrene (CL<jats:sub>app</jats:sub>), t<jats:sub>1/2,β</jats:sub> of styrene or excretion of MA and PGA on one hand, and the individual metabolic capacity on the other hand was found. Although other explanations cannot be excluded, this lack of correlation might be due to the high apparent blood clearance (1.4 1/ min) of styrene, indicating that styrene metabolism is liver–blood-flow-dependent. </jats:p>

CYP2E1 Metabolism of Styrene Involves Allostery

“…sible through a reciprocal Lineweaver-Burk plot of the data, which unevenly weighs data points and masks non-Michaelis-Menten behavior. For comparison to previous studies (Mendrala et al, 1993;Nakajima et al, 1994;Wenker et al, 2001), we recast data from our microsomal reactions as a Lineweaver-Burk plot shown in Fig. 8.…”

“…This degradative pathway occurs very slowly in water but is rapidly catalyzed by epoxide hydrolase. CYP2E1 is primarily responsible for the initial critical step in styrene activation to a reactive metabolite (Mendrala et al, 1993;Nakajima et al, 1994;Kim et al, 1997;Wenker et al, 2001), and thus, an understanding of the contribution of CYP2E1 to the metabolic clearance of styrene is necessary for adequately estimating risk associated with exposure to this pollutant.…”

“…Kinetic profiles for steady-state reactions demonstrated distinct high-and low-affinity enzyme activities. The highaffinity activity was attributed to CYP2E1 on the basis of correlative activity assays (Kim et al, 1997;Wenker et al, 2001) and inhibitor phenotyping (Koop, 1990;Wenker et al, 2001). Kinetic data were analyzed by the Michaelis-Menten equation to obtain V max and K m parameters used for modeling metabolic clearance (V max /K m ) of the pollutant (Mendrala et al, 1993;Nakajima et al, 1994;Wenker et al, 2001).…”

“…The highaffinity activity was attributed to CYP2E1 on the basis of correlative activity assays (Kim et al, 1997;Wenker et al, 2001) and inhibitor phenotyping (Koop, 1990;Wenker et al, 2001). Kinetic data were analyzed by the Michaelis-Menten equation to obtain V max and K m parameters used for modeling metabolic clearance (V max /K m ) of the pollutant (Mendrala et al, 1993;Nakajima et al, 1994;Wenker et al, 2001). This strategy demonstrated that a high-affinity (CYP2E1) activity was approximately 100-fold more efficient than a low-affinity activity, indicating that the metabolic efficiency of CYP2E1 dominates styrene metabolism (Wenker et al, 2001).…”

Estimation of absorption of aromatic hydrocarbons diffusing from interior materials in automobile cabins by inhalation toxicokinetic analysis in rats

“…Alveolar retention in humans inhaling these aromatic hydrocarbons was examined by many researchers (Astrand, 1975;Bardodej and Bardodejova, 1970;Carlsson, 1982;FiserovaBergerova, 1983;Hjelm et al, 1988Hjelm et al, , 1994Jakubowski and Wieczorek, 1988;Jarnberg et al, 1996;Kostrzewski et al, 1997;Liira et al, 1988;Lof et al, 1990a, b;Pezzagno et al, 1985Pezzagno et al, , 1988Riihimaki et al, 1979;Sedivec and Flek, 1976;Senczuk and Orlowski, 1978;Wallen et al, 1984Wallen et al, , 1985Wenker et al, 2001;Wieczorek and Piotrowski, 1985;Wigaeus et al, 1983Wigaeus et al, , 1984. However, the levels of retention, which were presumed to vary markedly with time immediately after the start of inhalation, were not described in detail in their reports.…”