Protoporphyrin IX-Induced Impairment of Biliary Lipid Secretion in the Rat

Pérez‐Barriocanal, Fernando; Redondo-Torres, J. G.; Villanueva, Gloria R.; Arteche, Elena; Berenson, Malcolm M.; Marin, José J.G.

doi:10.1042/cs0770473

Cited by 11 publications

(3 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Protoporphyrin IX (PPIX), the penultimate metabolite of heme biosynthesis, has been implicated in cholestasis of various etiologies in mice and humans. The PPIX is cytotoxic (Weiss et al, 2003) and reduces bile flow, leading to cholestasis and liver injury (Perez-Barriocanal et al, 1989). Protoporphyrin IX accumulation is associated with liver injury in mice when exogenously applied and with genetic or pharmacologic dysfunction of the heme biosynthetic pathway (Davies et al, 2005;Lyoumi et al, 2011).…”

mentioning

confidence: 99%

The Isoniazid Metabolites Hydrazine and Pyridoxal Isonicotinoyl Hydrazone Modulate Heme Biosynthesis

Brewer

Yang

Edwards

et al. 2018

Toxicological Sciences

View full text Add to dashboard Cite

In a mouse model, rifampicin and isoniazid combination treatment results in cholestatic liver injury that is associated with an increase in protoporphyrin IX, the penultimate heme precursor. Both ferrochelatase (FECH/Fech) and aminolevulinic acid synthase 1 (ALAS1/Alas1) are crucial enzymes in regulating heme biosynthesis. Isoniazid has recently been reported to upregulate Alas1 but downregulate Fech protein levels in mice; however, the mechanism by which isoniazid mediates disruption of heme synthesis has been unclear. Two metabolites of isoniazid, pyridoxal isonicotinoyl hydrazone (PIH, the isoniazid-vitamin B6 conjugate) and hydrazine, have been detected in the urine of humans treated with isoniazid. Here we show that, in primary human hepatocytes and the human hepatocellular carcinoma cell line HepG2/C3A, (1) isoniazid treatment increases Alas1 protein levels but decreases Fech levels; (2) hydrazine treatment upregulates Alas1 protein and Alas1 mRNA levels; (3) PIH treatment decreases Fech protein levels, but not Fech mRNA levels; and (4) PIH is detected after isoniazid treatment, with levels increasing further when exogenous vitamin B 6 analogs are coadministered. In addition, the PIH-mediated downregulation of human FECH is associated with iron chelation. Together, these data demonstrate that hydrazine upregulates ALAS1, whereas PIH downregulates FECH, suggesting that the metabolites of isoniazid mediate its disruption of heme biosynthesis by contributing to protoporphyrin IX accumulation.

show abstract

mentioning

confidence: 99%

The Isoniazid Metabolites Hydrazine and Pyridoxal Isonicotinoyl Hydrazone Modulate Heme Biosynthesis

Brewer

Yang

Edwards

et al. 2018

Toxicological Sciences

View full text Add to dashboard Cite

show abstract

“…The liver, specifically the hepatobiliary system, is responsible for PPIX excretion from the body (Sachar et al, 2016a). Due to the hydrophobic nature of PPIX, high levels of PPIX in bile will precipitate and block bile ducts, impairing bile flow and resulting in damages to both hepatocytes and cholangiocytes (Perez-Barriocanal et al, 1989). Eventually, PPIX-mediated bile duct blockage can cause hepatic inflammation, fibrosis, and cirrhosis, mainly around portal areas (zone 1) (Anstey and Hift, 2007).…”

Section: Ppix-mediated Hepatotoxicitymentioning

confidence: 99%

Roles of the ABCG2 Transporter in Protoporphyrin IX Distribution and Toxicity

Qi,

Gu,

Zhu

et al. 2024

Drug Metab Dispos

View full text Add to dashboard Cite

ATP-binding cassette transporter subfamily G member 2 (ABCG2) is a membrane-bound transporter responsible for the efflux of various xenobiotics and endobiotics, including protoporphyrin IX (PPIX), an intermediate in the heme biosynthesis pathway. Certain genetic mutations and chemicals impair the conversion of PPIX to heme and/or increase PPIX production, leading to PPIX accumulation and toxicity. In mice, deficiency of ABCG2 protects against PPIX-mediated phototoxicity and hepatotoxicity by modulating PPIX distribution. In addition, in vitro studies revealed that ABCG2 inhibition increases the efficacy of PPIX-based photodynamic therapy by retaining PPIX inside target cells. In this review, we discuss the roles of ABCG2 in modulating the tissue distribution of PPIX, PPIX-mediated toxicity, and PPIXbased photodynamic therapy. Significance statementThis review summarized the roles of ABCG2 in modulating PPIX distribution and highlighted the therapeutic potential of ABCG2 inhibitors for the management of PPIX-mediated toxicity.

show abstract

“…In these cases, severe liver damage could be difficult to treat and sometimes requires liver transplantation. In experimental models, PPIX causes marked cholestasis [99] with impaired biliary lipid secretion [100]. Bile acids with detergent ability, such as taurocholic acid, have been found to enhance PPIX metabolism and ameliorate biliary function [100,101].…”

Section: Aggressions To the Canalicular Membrane And Bile Ductsmentioning

confidence: 99%

Etiopathogenesis and pathophysiology of cholestasis

et al. 2022

View full text Add to dashboard Cite

Normal hepatobiliary function depends on an adequate bile flow from the liver through the biliary tree to the gallbladder, where bile is stored and concentrated, and from the gallbladder to the duodenum when it is required for the digestive process. Interruption of this secretory function results in partial or complete cholestasis, which is accompanied by important repercussions due to the lack of bile acids in the intestine and their regurgitation from hepatocytes to blood together with potentially toxic compounds that are normally eliminated in bile. The presence of active and selective transporter proteins located at both poles of the plasma membrane of hepatocytes, cholangiocytes, and epithelial cells of the ileal mucosa, together with the ability of hepatocytes to synthesize bile acids from cholesterol, enables the so-called bile acid enterohepatic circulation, which is essential in liver and gastrointestinal tract physiology. The presence in the ducts of the biliary tree of agents reducing their luminal diameter by external compression or space-occupying obstacles, either in the duct wall or its lumen, can result in total or partial obstructive cholestasis. The clinical impact and management of cholestasis are different depending on the intrahepatic or extrahepatic location of the obstacle. Thus, surgical interventions can often be helpful in removing extrahepatic obstructions and restoring normal bile flow to the duodenum. In contrast, hepatocyte or cholangiocyte damage, either global, restricted to subcellular compartments, or more specifically affecting the elements of the canalicular secretory machinery, may result in hepatocellular cholestasis or cholangiopathies. In these cases, bile flow interruption is usually partial and, except for extremely severe cases when liver transplantation is required, these patients often treated with pharmacological agents, such as ursodeoxycholic acid (UDCA) and rifampicin. The present review gathers updated information on the etiopathogenesis and pathophysiological aspects of different types of cholestasis.

show abstract

Protoporphyrin IX-Induced Impairment of Biliary Lipid Secretion in the Rat

Cited by 11 publications

References 0 publications

The Isoniazid Metabolites Hydrazine and Pyridoxal Isonicotinoyl Hydrazone Modulate Heme Biosynthesis

The Isoniazid Metabolites Hydrazine and Pyridoxal Isonicotinoyl Hydrazone Modulate Heme Biosynthesis

Roles of the ABCG2 Transporter in Protoporphyrin IX Distribution and Toxicity

Etiopathogenesis and pathophysiology of cholestasis

Contact Info

Product

Resources

About