Extrahepatic metabolism at the body's internal-external interfaces.

Area of Science:

• Pharmacology and Toxicology
• Biochemistry
• Molecular Biology

Background:

• Xenobiotic metabolizing enzymes (XMEs) are crucial for drug and toxin processing.
• While liver XME expression is well-studied, extrahepatic XME roles in tissue-specific toxicity are less understood.
• Extrahepatic XMEs can cause local adverse effects like organ toxicities, allergies, and cancer.

Purpose of the Study:

• To review the expression of Phase I and Phase II XMEs and transporters in extrahepatic tissues.
• To highlight the role of these enzymes and transporters at the body's internal-external interfaces (lung, skin, intestine, kidney, bladder).
• To discuss regulatory mechanisms of XME expression and the knowledge gaps in their ontogeny.

Main Methods:

• Literature review summarizing current knowledge on XME and transporter expression.
• Focus on specific extrahepatic tissues: lung, skin, intestinal epithelium, kidney, and bladder.
• Analysis of Phase I (e.g., CYPs, epoxide hydrolases) and Phase II (e.g., UGTs, GSTs, NATs, SULTs) enzymes and transporters.

Main Results:

• Lung: Significant Phase I enzymes (CYPs, epoxide hydrolases); limited conjugation.
• Skin: Predominantly Phase II enzymes (UGTs, GSTs, NAT1) for detoxification.
• Intestine: High levels of transporters, CYP3A4/5, and Phase II enzymes (UGTs, NATs, SULTs).
• Kidney: Conjugation and transporters critical for excretion.
• Bladder: CYPs and NAT1 involved in carcinogen activation.
• XME expression is regulated by nuclear receptors, epigenetics, and microRNAs.

Conclusions:

• Extrahepatic XMEs and transporters play vital roles in local metabolism and toxicity.
• Understanding tissue-specific XME expression and ontogeny is crucial but remains fragmentary.
• Further research is needed to elucidate the developmental aspects of extrahepatic XME expression.