Do you agree that the depletion of glutathione (GSH) with increasing doses and duration of exposure is consistent with GSH conjugation being a predominant metabolic pathway for 1,3-D? (please explain)

Kinetics of 1-3D show non-linearity that is representative of enzymatic saturation or cofactor depletion. To distinguish between the two, an enzyme kinetic for GST pathway could have been made to determine if saturation could explain the observed non-linearity. Data shown in figure 2, show roughly a 50% depletion of GSH in lungs, but this uncertain if this is sufficient to explain this non-linearity.

It is clear that the levels of GSH in this portal-of-entry tissue were significantly depleted at 30 ppm and above. This depletion is consistent with the requirement of glutathione for 1,3-D metabolic clearance. Similar depletion has been found following repeated inhalation exposures to chemicals that undergo glutathione based metabolism such as ethylene oxide, propylene oxide, naphthalene etc.,

The non linearity in the clearance of 1,3-D is consistent with saturation of GSH conjugation. This suggests GSH conjugation being a predominant metabolic pathway.

The main metabolites found in the urine are in accordance with the GSH metabolic pathway. Furthermore, there is a direct effect of the GSH depletion on the blood kinetics of the compound. Accordingly, the relevant nonlinearity that was observed in the blood kinetics between about 10-60 ppm is quite consistent with the depletion of glutathione between about 10-60 ppm reported in lung tissues.