Imaging of hepatic drug transporters with [131I]6-ß-iodomethyl-19-norcholesterol.

We examined whether [131I]6-ß-iodomethyl-19-norcholesterol (NP-59), a cholesterol analog, can be used to measure function of hepatic drug transporters. Hepatic uptake of NP-59 with and without rifampicin was evaluated using HEK293 cells expressing solute carrier transporters. The stability of NP-59 was evaluated using mouse blood, bile, and liver, and human liver S9. Adenosine triphosphate-binding cassette (ABC) transporters for bile excretion were examined using hepatic ABC transporter vesicles expressing multidrug resistance protein 1, multidrug resistance-associated protein (MRP)1-4, breast cancer resistance protein (BCRP), or bile salt export pump with and without MK-571 and Ko143. Single photon emission computed tomography (SPECT) was performed in normal mice injected with NP-59 in the presence or absence of Ko143. Uptake of NP-59 into HEK293 cells expressing organic anion transporting polypeptide (OATP)1B1 and OATP1B3 was significantly higher than that into mock cells and was inhibited by rifampicin. NP-59 was minimally metabolized in mouse blood, bile, and liver, and human liver S9 after 120 min of incubation. In vesicles, NP-59 was transported by MRP1 and BCRP. Excretion of NP-59 into bile via BCRP was observed in normal mice with and without Ko143 in the biological distribution and SPECT imaging. NP-59 can be used to visualize and measure the hepatic function of OATP1B1, OATP1B3, and BCRP.

Practical considerations in the scintigraphic evaluation of endocrine hypertension. The adrenal cortex and medulla.

A nuclear scan maps the distribution of a radiopharmaceutical that is specific for a physiologic property of a targeted tissue. As such, it is not limited by the anatomic changes necessary for CT and MR scans. It is just because of this that maps of specific metabolic precursors of adrenal medullary and cortical hormones offer information crucial to the therapeutic strategy of endocrine hypertension. NP-59 and MIBG scans can specify the nature of abnormalities revealed by anatomic images and because of the ease of surveying the whole body can give transcendent information about lesions remote from the adrenals. In instances when the origin of endocrine hypertension is not forthcoming from CT or MR imaging or when the anatomic and biochemical findings are in conflict, NP-59 or MIBG can almost always provide the answer.

Cellular internalization, transport, and esterification of iodine-125-NP59 by MA-10 Leydig tumor cells.

The present studies were directed toward understanding the cellular processing of the cholesterol analogue, NP59. NP59 readily entered MA-10 Leydig tumor cells. The cholesterol analogue entered the cells by binding to the plasma membrane and becoming internalized along with plasma membrane cholesterol. Internalized NP59 was readily esterified to NP59 ester. Transport of NP59 within the cell was indistinguishable from transport of cholesterol. Cholesterol and NP59 transport were under the control of cAMP, however, only cholesterol entered the mitochondria and was converted into progesterone. Thus, internalized NP59 could not be removed from the cell by conversion into steroid hormones. Esterified NP59 was metabolically inert and could not be converted back to free NP59 and free fatty acid. Since NP59 was not a substrate for the cholesteryl ester hydrolase, it became trapped in the cell as NP59 ester.

Scintigraphic endocrine mimicry.

The control of hormone secretion and substrate uptake by the thyroid and inner adrenal cortex is similar because both glands undergo hypothalamic-pituitary trophic hormone modulation and negative feedback by their respective major secretory products: thyroid hormone and cortisol, respectively. As a result of these parallel mechanisms of endocrine function, thyroidal accumulation of radioiodine or Tc-99m pertechnetate and adrenal cortical accumulation of I-131-6 beta-iodomethylnorcholesterol (NP-59) and other radiocholesterol analogs are strikingly similar. The patterns of imaging of these glands are thus functional maps of the process(es) of substrate accumulation and depict the endocrine pathophysiology of these glands in a variety of dysfunctional states. The well-recognized patterns of thyroid imaging can be shown analogous to those of the adrenal cortex.