4-Hydroxyphenylpyruvate dioxygenase (HPPD) is essential for plant carotenoid biosynthesis; and is also present in mammals where it is involved in the catabolism of tyrosine, an amino acid derived from dietary proteins. However, inhibition of the mammalian orthologs of HPPD can result in accumulation of hydroxyphenylpyruvic acid (HPPA) and systemic tyrosine (tyrosinemia). This can result in a spectrum of tyrosine-mediated effects including ocular lesions, glomerulonephropathy, liver and kidney  weight effects in systemic toxicity studies and  delayed ossification, litter loss and low pup survival in developmental and reproductive toxicity studies. Species differences in sensitivity to HPPD-inhibiting herbicides have been observed in toxicity studies. Tyrosine aminotransferase (TAT) catalyzes the conversion of tyrosine to HPPA and its activity varies among mammalian species. Species differences also exist in the ability to utilize alternative pathways for tyrosine catabolism when HPPD is inhibited.  In this work, we utilise an in silico approach to rationalise these species differences in tyrosinemia and understand species relevance to human health risk assessment.<br/><br/>We developed a systems pharmacodynamic model of mammalian HPPD inhibition to predict thresholds for toxicity and allow quantitative cross-species extrapolation.  A mechanistic pharmacokinetic (PK)-pharmacodynamic (PD) model for mammalian HPPD inhibition, consisting of a systems-based description of the catabolic pathway for tyrosine, was coupled with HPPD inhibitor PK. Tyrosine in vivo time course data (in rat) from over 100 HPPD inhibitor molecules were used for model development and validation. In vitro potency assay data were also used to quantify relevant species-specific enzymatic activities allowing cross species extrapolation of tyrosinemia potential. The final model takes as inputs a single dose PK curve along with in vitro potency descriptors which is capable of predicting blood tyrosine levels following HPPD inhibition. Model parameter adjustments then allow for interspecies extrapolation and thus an evaluation of potential risks associated with HPPD inhibitor exposures in human populations.

Systems pharmacodynamic modelling of 4-hydroxyphenylpyruvate dioxygenase inhibition: Predicting tyrosinaemia

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