Extrahepatic metabolism at the body's internal–external interfaces

Abstract

In general, xenobiotic metabolizing enzymes (XMEs) are expressed in lower levels in the extrahepatic tissues than in the liver, making the former less relevant for the clearance of xenobiotics. Local metabolism, however, may lead to tissue-specific adverse responses, e.g. organ toxicities, allergies or cancer. This review summarizes the knowledge on the expression of phase I and phase II XMEs and transporters in extrahepatic tissues at the body's internal-external interfaces. In the lung, CYPs of families 1, 2, 3 and 4 and epoxide hydrolases are important phase I enzymes, while conjugation is less relevant. In skin, phase I-related enzymatic reactions are considered less relevant. Predominant skin XMEs are phase II enzymes, whereby glucuronosyltransferases (UGT) 1, glutathione-S-transferase (GST) and N-acetyltransferase (NAT) 1 are important for detoxification. The intestinal epithelium expresses many transporters and phase I XME with high levels of CYP3A4 and CYP3A5 and phase II metabolism is mainly related to UGT, NAT and Sulfotransferases (SULT). In the kidney, conjugation reactions and transporters play a major role for excretion processes. In the bladder, CYPs are relevant and among the phase II enzymes, NAT1 is involved in the activation of bladder carcinogens. Expression of XMEs is regulated by several mechanisms (nuclear receptors, epigenetic mechanisms, microRNAs). However, the understanding why XMEs are differently expressed in the various tissues is fragmentary. In contrast to the liver - where for most XMEs lower expression is demonstrated in early life - the XME ontogeny in the extrahepatic tissues remains to be investigated.

N-Monosubstituted Methoxy-oligo(ethylene glycol) Carbamate Ester Prodrugs of Resveratrol

“…Evolution has endowed organisms with a powerful apparatus designed to detoxify "xenobiotic" substances which reach the cytoplasm [1][2][3]. These compounds tend to be hydrophobic/apolar to pass the cell membrane.…”

Phase II Metabolism in Human Skin: Skin Explants Show Full Coverage for Glucuronidation, Sulfation,N-Acetylation, Catechol Methylation, and Glutathione Conjugation

“…Despite this potential importance, cutaneous drug metabolism is generally overlooked and rarely discussed during drug development. A better understanding of skin metabolism could also close the general in vitro-in vivo extrapolation gap for drugs where extensive extrahepatic metabolic clearance is suspected (Hiraoka et al, 2005;Gundert-Remy et al, 2014).…”

“Target-Site” Drug Metabolism and Transport

“…3). P450 expression in various pulmonary cell lines representing the complex heterogenous cell layers of the lung has been reported, and variable P450 isozyme levels are thought to be expressed across the pulmonary cell layers (Gundert-Remy et al, 2014). Thus, Somers et al (2007) reported modest human lung parenchymal levels of CYP1A1, 2J2, and 2A5, but lower expression levels compared with the liver.…”

“…Numerous studies have shown modest expression of CYP1A1 in the bronchus and lung, with highly induced levels of the enzyme in smokers (Anttila et al, 2011). dmd.aspetjournals.org P450 expression in the lung is highly relevant in the context of endogenous steroid homeostasis as well as activation of tobacco-specific lung carcinogens (Hecht, 2008;Gundert-Remy et al, 2014).…”

“…Organ-specific disposition is especially important for specific organs that are the target site for the compound. The human lung is one such organ with respect to disposition of drugs (e.g., lung cancer chemotherapy), xenobiotics (e.g., tobacco-specific carcinogens), and endobiotics (e.g., steroids) (Hecht, 2008;Gundert-Remy et al, 2014).…”