Leber hereditary optic neuropathy—new insights and old challenges

Graefe's Archive for Clinical and Experimental Ophthalmology - Leber hereditary optic neuropathy (LHON) is the most common primary mitochondrial DNA (mtDNA) disorder with the majority of...     

Evaluation of the potential impact of age- and gender-specific lung morphology and ventilation rate on the dosimetry of vapors

In recent years, there have been growing concerns that due to differences, both pharmacokinetic and pharmacodynamic, between children and adults, children could be at greater risk of adverse effects following chemical exposure. The specific goal of this study was to demonstrate an approach for using physiologically based pharmacokinetic (PBPK) modeling to compare inhalation dosimetry in the adult and the child of both males and females. Three categories of gases were considered: rapidly and irreversibly reactive in the respiratory tract (ozone), relatively water-soluble and nonreactive (isopropanol), and relatively water-insoluble and nonreactive (styrene, vinyl chloride, and perchloroethylene). The nonreactive chemicals were also selected because they are metabolized in the respiratory tract. The age-related changes observed for the estimated dose metrics were a function of the physiochemical properties of the inhaled vapor and their interactions in the body. Blood concentrations estimated for all vapors, either poorly metabolized (e.g., PERC), moderately metabolized (e.g., ST), or highly metabolized vapors (e.g., IPA and VC), varied less than a factor of two between infants and adults. These changes, moreover, were confined to the first year after birth, a relatively short window compared to the total lifespan of the individual. In contrast, circulating metabolite concentrations estimated in the blood, as well as amounts metabolized in the liver and lung, appeared to be a strong function of age, due to their dependence on the maturity of the pertinent metabolic enzyme systems.     

Physiologically based clearance/extraction models for compounds metabolized in the nose: an example with methyl methacrylate

Airstream clearance (with units of volume/time) is the volumetric flow from which chemical would have to be completely removed to account for the net loss in the nose. Extraction is the proportion of airflow from which the chemical is completely removed. Over the past several years we have developed physiologically based clearance-extraction (PBCE) models for the nose to assess the physiological, biochemical, and anatomical factors that control airstream clearance. A generic clearance equation was derived for single airway/tissue compartments that had a separate air region and either one, two, or three underlying tissue regions. For all of these structures, airstream clearance (Cl(sys)) has a common form-Equation (1)-related to tissue clearance (Cltot), gas-phase diffusional clearance (PAgas), airflow (Q), and the mucus air partition coefficient (Hmuc:a). Clsys = CltotHm:aPAgasQ/CltotHm:a(Q + PAgas) + PAgasQ. A physiologically based clearance-extraction (PBCE) model for the whole nose combined three separate nasal tissue regions, each with a four-compartment tissue stack (air, mucus, epithelial tissue, and submucosal region). A steady-state solution of the PBCE model successfully described literature results on the steady-state extraction of methyl methacrylate (MMA) and several other metabolized vapors. Model-derived tissue dosimetry estimates, that is, the amount of MMA metabolized in the target epithelial compartment of the olfactory region, for rats and humans provide dosimetric adjustment factors (DAFs) required in calculating a human reference concentration (RfC) from rodent studies. Depending on the assignment of esterase activities to sustentacular and submucosal regions, the DAFs from the PBCE model varied between 1.6 and 8.0, compared to the default value of 0.145. From the experience with MMA, a minimal data set could be defined for building the PBCE model. It consists of mucus:air and blood:air partition coefficients, metabolic constants for enzymatic hydrolysis in nasal tissues from rat and human tissues, immunohistochemistry of the distribution of these activities in rats and human olfactory tissues, and extraction studies in anesthetized rats to assess the total nasal metabolism of the test compound.     

Regional distribution and kinetics of vinyl acetate hydrolysis in the oral cavity of the rat and mouse.

Vinyl acetate is an ester that is used to make polyvinyl acetate based polymers that are used in the manufacture of latex paints and adhesives. Chronic oral exposure to high concentrations of vinyl acetate induces oral tumors in rodents. Since carboxylesterase-dependent hydrolysis of VA to acetic acid and acetaldehyde has been implicated in the nasal inhalation carcinogenesis of this ester, the potential for oral mucosa of the F344 rat and BDF mouse to hydrolyze VA was examined. Homogenates were prepared by scraping the mucosa from four regions of the oral cavity: dorsal interior (all tissues interior to the teeth), dorsal tongue surface, ventral interior (sublingual area and lower interior tissues) and exterior (all tissues exterior to the teeth). The oral cavity was rinsed once with saline prior to dissection to determine if oral secretions possessed metabolic capacity. Aliquots of the homogenates or rinse fluid were incubated for 30 min with varying concentrations of vinyl acetate (0.05-10 mM), and the production of acetaldehyde was quantitated by HPLC. All tissue regions possessed VA hydrolysis activity. In both species the hydrolysis activity was greatest in the dorsal interior region (Vmax of 90 and 6 nmol/min in the rat and mouse, respectively, Km values of 0.5 and 0.9 mM). Activity in the other oral regions was 2-15-fold lower. Activity was observed in the rinse fluid, but was 20-fold or more lower than the dorsal interior region. Finally, solutions of vinyl acetate were placed in the mouth of anesthetized rats for 10 min and then analyzed for acetaldehyde concentrations. Acetaldehyde was detected in these solutions providing evidence that metabolism of this ester occurs in vivo in oral tissues.     

Dose-response modeling of cytochrome p450 induction in rats by octamethylcyclotetrasiloxane.

Inhalation of octamethylcyclotetrasiloxane (D4) induces CYP2B1/2 protein and causes liver enlargement. We have developed a pharmacodynamic (PD) extension to a physiologically based pharmacokinetic (PBPK) model to characterize these dose-response behaviors. The PD model simulates interactions of D4 with a putative receptor, leading to increased production of cytochrome P450 2B1/2. Induction was modeled with a Hill equation with dissociation constant, Kd, and Hill coefficient, N. Both a 1- and a 5-compartment liver model were evaluated. The PBPK model provided excellent simulations of tissue D4 and hepatic CYP2B1/2 protein concentrations following 6 h/day, 5-day inhalation exposures to 0, 1, 7, 30, 70, 150, 300, 500, 700, or 900 ppm D4. Either the 1- or 5-compartment liver model could accurately simulate increases in CYP2B1/2 protein in the liver. With a 1-compartment liver, Kd and N were 0.67 microM (free liver concentration) and 1.9, respectively. The 5-compartment model used higher N-values (approximately 4.0) and varied Kd between compartments. The fitted 5-compartment model parameters were Kd = 0.67 microM in the midzonal compartment with geometric differences in Kd between compartments of 2.9. On the basis of unbound (free) plasma concentrations, D4 appeared to be a higher potency inducer than phenobarbital (PB). Dose-response curves for increased liver weights had N/mS 1.0 and Kd/mS 3.4 microM, very different values from those for enzyme induction. Exposure concentration leading to a 0.1% increase in CYP2B1/2 protein predicted by the 1- and 5-compartment models were 2.1 ppm and 5.1 ppm, respectively. The 1- and 5-compartment liver models provided very similar fits to the whole liver induction data, excluding the lowest dose, but the 5-compartment liver model had the additional advantage of simultaneously describing the regional induction of CYP2B1/2.