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NOVEL INSIGHTS INTO 3,5-DIETHOXYCARBONYL-1,4-DIHYDROCOLLIDINE (DDC)-INDUCED PROTOPORPHYRIN IX ACCUMULATION AND LIVER INJURY

Gu, Ruizhi (2022) NOVEL INSIGHTS INTO 3,5-DIETHOXYCARBONYL-1,4-DIHYDROCOLLIDINE (DDC)-INDUCED PROTOPORPHYRIN IX ACCUMULATION AND LIVER INJURY. Master's Thesis, University of Pittsburgh. (Unpublished)

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Abstract

3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) is a porphyrinogenic agent that causes protoporphyrin IX (PPIX) accumulation in the liver and consequently liver damage. DDC-mediated PPIX accumulation is thought to be liver specific by inducing hepatic 5'-aminolevulinate synthase 1, the rating limiting enzyme in the heme biosynthesis pathway, resulting in the increase of PPIX production. In addition, it has been proposed that the hepatic cytochromes P450 (CYPs)-mediated metabolism of DDC is involved in the formation of N-methyl protoporphyrin IX (N-Me PPIX), a potent inhibitor of ferrochelatase that converts PPIX into heme, leading to further PPIX accumulation in the liver. However, the role of hepatic CYPs in DDC-mediated N-Me PPIX production remains unclear. The current work aimed to fill this knowledge gap by using the liver-specific NADPH-cytochrome P450 reductase-null (LCN) mouse model, in which hepatic CYPs are functionally deficient. We found that LCN mice did not attenuate DDC-mediated N-Me PPIX production, suggesting that N-Me PPIX formation is independent on hepatic CYPs. We next used a metabolomic approach to explore the extrahepatic effects of DDC. High levels of PPIX and N-Me PPIX were found in the sera of mice treated with DDC. Our further analyses revealed that the bone marrow is a target of DDC that contributes to the production of PPIX and N-Me PPIX, which can be delivered to the liver and result in liver injury. In summary, DDC-mediated N-Me PPIX formation and PPIX accumulation is not liver specific, and instead the bone marrow seems the major source of N-Me PPIX and PPIX after DDC exposure. Moreover, our data suggest that DDC-mediated formation of N-Me PPIX is independent on hepatic CYPs.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Gu, RuizhiRUG25@pitt.eduRUG25
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairMa, Xiaochaomxiaocha@pitt.edumxiaocha
Committee MemberZhang, Minmiz45@pitt.edumiz45
Committee MemberBrixius-Anderko, Simonesib51@pitt.edusib51
Date: 14 April 2022
Date Type: Publication
Defense Date: 7 April 2022
Approval Date: 14 April 2022
Submission Date: 8 April 2022
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 37
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: DDC; PPIX; N-Me PPIX; CYP; bone marrow; liver injury
Date Deposited: 14 Apr 2022 12:49
Last Modified: 14 Apr 2022 12:49
URI: http://d-scholarship.pitt.edu/id/eprint/42562

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