Disease relevance of Hpd

• We have cloned and overexpressed rat 4-hydroxyphenylpyruvate dioxygenase (4HPPD) in Escherichia coli [1].
• Congenital HPD deficiency is a rare, relatively benign condition known as hereditary type III tyrosinemia [2].
• Uptake, toxicity, and morphologic damage following exposure to HPD PDT were evaluated [3].
• The authors have established a rat urothelial cell model for use in comparing and contrasting the effects of HPD photodynamic therapy (PDT) in normal (RBL-01) and transitional cell carcinoma (AY27) bladder cell lines [3].
• In Nx rats on a HPD, the development of secondary hyperparathyroidism (286 +/- 19 pg/ml in the Nx-IPTG-HPD group) prevented a decrease in serum calcitriol levels (68 +/- 7 pg/ml) [4].

High impact information on Hpd

• Both cell lines displayed increased toxicity with higher concentrations of HPD; however, the AY27 cells were more susceptible to the toxic effects of HPD PDT than the RBL-01 cells at the higher HPD doses studied (25 and 50 micrograms/ml) [3].
• Both cell lines demonstrated fast initial uptake of HPD followed by slower uptake over the time studied [3].
• The initial morphologic change following HPD PDT was damage to mitochondria [3].
• They also bear minimal or no Ag-F alloantigen, a peripheral T cell marker, and they express Ia-like products analogous to those of the mouse I-A subregion but not of the I-E/C subregion [5].
• RESULTS: Vitamin D-binding protein, paraoxonase, cellular retinol-binding protein, malate dehydrogenase, F-protein, and purine nucleoside phosphorylase were identified as empirically confirmed serum markers for hepatic effects in drug-treated rats [6].

Chemical compound and disease context of Hpd

• Trypan blue exclusion was used for determination of the toxicity of several HPD concentrations (1, 10, 25, and 50 micrograms/ml) with increasing duration of incubation with HPD (0, 1, 2, 4, 12, 24, and 48 hours) [3].
• This observed chemically induced tyrosinemia established that this compound perturbs tyrosine catabolism and suggested that the causal effect is the inhibition of 4-hydroxyphenylpyruvate dioxygenase (HPPD) [7].
• These results suggest that CLT (160 micrograms/kg) primarily acts on cholecystokinin-A receptor in the brain, exerts some modulatory influence on HPD binding to striatal DA receptors via unknown neural pathways and, consequently, inhibits HPD catalepsy [8].
• Ceruletide (CLT: 160 micrograms/kg, SC) produced a relatively long-lasting inhibition of haloperidol (HPD: 2 mg/kg, PO) catalepsy in rats [8].
• The disadvantages of using hematoporphyrin derivative rather than its individual components in studies of HPD uptake and photosensitization in the brain are discussed [9].

Biological context of Hpd

• Tissue distribution, intracellular localization and proteolytic processing of rat 4-hydroxyphenylpyruvate dioxygenase [2].
• In contrast, HPD rats had an elevated Pi fractional excretion (41 +/- 4%, p < 0.001), whereas reabsorbed phosphate per min corrected for the glomerular filtration rate was not increased by a Pi load.(ABSTRACT TRUNCATED AT 250 WORDS)[10]
• By day 15, the percentage of cells in the S phase in NPD and HPD were not different [11].
• The results show that an HPD results in the stimulation of the parathyroid cell cycle independently of changes in calcium and calcitriol [11].
• The catalytic subunit fraction in which G/F protein was totally lacking was also activated by forskolin [12].

Anatomical context of Hpd

• In addition, we show that HPD is abundantly expressed in neurons in the cortex, cerebellum and hippocampus [2].
• By using immunoelectron microscopy and confocal laser scanning microscopy, we provide evidence that HPD contrary to earlier assumptions specifically localizes to membranes of the endoplasmic reticulum and the Golgi apparatus [2].
• Multicellular spheroids as an in vitro model system for photoradiation therapy in the presence of Hpd [13].
• The differential detergent solubilization of adenylate cyclase and polypeptides ADP-ribosylated with cholera toxin suggests an excess of G/F protein relative to adenylate cyclase in rat pancreatic plasma membranes [14].
• Clearance experiments and brush border membrane studies were performed on 21-d-old rats weaned early on d 16 onto a low phosphate diet (LPD, 0.19 g/100 g), a normal phosphate diet (control, 0.78 g/100 g), or a high phosphate diet (HPD, 1.5 g/100 g) [10].

Associations of Hpd with chemical compounds

• The soluble, active recombinant enzyme was shown to contain both 4HPPD and alpha-ketoisocaproate dioxygenase (alpha KICD) activity [1].
• 4-hydroxyphenylpyruvate dioxygenase (HPD) is an important enzyme involved in tyrosine catabolism [2].
• Even in N rats on a HPD, high PTH levels (67 +/- 8 pg/ml in the N-IPTG-HPD group) were required to maintain normal serum calcitriol levels (69 +/- 4 vs. 56 +/- 6 pg/ml in Nx-IPTG-HPD and Nx-PTHR-HPD groups, respectively; P < 0.05) [4].
• These results indicate that proteolytic cleavage of the F protein, with a single arginine residue at the cleavage site, occurs extracellularly in the allantoic cavity of chick embryos and in the bronchial lumen of rats [15].
• CLT (160 micrograms/kg) significantly inhibited HPD (2 mg/kg)-induced increase in dopamine (DA) release from the rat striatum [8].

Other interactions of Hpd

• The results seen with the solubilized enzyme, with either Lubrol PX or cholate, indicate that the effects of forskolin on the cyclase do not require either G/F protein or calmodulin and the results of our study of brain enzymes support this view [12].

Analytical, diagnostic and therapeutic context of Hpd

• However, upon truncation of the 14 amino acids at the C-terminus by site-directed mutagenesis, the resulting mutant enzyme (rat F antigen) exhibited complete loss of 4HPPD and alpha KICD activities [1].
• The mean urinary dopamine excretion for the 4 days of HPD significantly increased to 4.5 +/- 0.5 microgram/day in the group with chronic bilateral renal denervation and 3.7 +/- 0.2 microgram/day in the group with innervated kidneys [16].
• Moreover, the photosensitization of mitochondria by the tumor-localizing porphyrin dimer/oligomer fraction of 'HPD' was not inhibited by benzodiazepines in cell culture [17].
• Young male albino rats (120+/-5 g) were kept for 30 d on the following synthetic diets--High Protein Diet (HPD): 59% casein; Low Protein Diet (LPD): 5% casein; High Fat Diet (HFD): 51% fat; and Standard Diet (SD); 19% casein, 11% fat, and 60% sucrose [18].
• Free-flow micropunctures under acute Pi infusion were made at elevated but similar filtered loads of Pi: LPD, 6.07 +/- 0.29 (n, 32); HPD 5.34 +/- 0.24 (n, 33) micromol/kidney per min [19].

References