Letter to the Editor: Causality dilemma of cytochrome P450 1A2 reduction in neonatal cholestasis

Abstract

This letter discusses the pilot study by Kotb et al published in World Journal of Clinical Pediatrics, which identifies significantly reduced serum cytochrome P450 1A2 (CYP1A2) levels in neonates with biliary atresia and neonatal hepatitis compared to healthy controls. While these findings highlight a potential role for detoxification mechanisms in neonatal cholestasis, critical methodological issues regarding the interpretation of results warrant attention. The primary concern is the causality dilemma; it is crucial to distinguish between an innate ‘defect’ (congenital deficiency) and ‘downregulation’ (secondary suppression). Low CYP1A2 levels may be a secondary consequence of systemic inflammation rather than an inherent susceptibility factor. Furthermore, the reliance on enzyme-linked immunosorbent assay for protein abundance lacks the resolution of functional activity assays. Future research should integrate single-cell multi-omics and gut-metabolite signaling to decode the complexity of the hepatic microenvironment.

Key Words: Cytochrome P450 1A2; Neonatal cholestasis; Biliary atresia; Detoxification; Neonatal

Core Tip: This letter provides a critical perspective on the findings of Kotb et al regarding cytochrome P450 1A2 levels in neonatal cholestasis. We highlight the causality dilemma, suggesting that reduced enzyme levels may be a secondary consequence of inflammation and liver injury rather than an inherent “defect”. Furthermore, we address methodological concerns, including the lack of genetic validation and the limitations of using enzyme-linked immunosorbent assay to estimate functional metabolic capacity. We emphasize the need to explicitly differentiate between primary genetic defects and secondary downregulation induced by liver injury. We propose incorporating functional probe drug assays (e.g., caffeine clearance) and transcriptomic profiling to validate these phenotypic observations, ensuring safer pharmacological management.

TO THE EDITOR

The neonatal period is a phase of rapid transition for liver physiology, where both enzymatic and immunological landscapes undergo dramatic shifts. Understanding the physiological, morphological, and immunological changes that occur in the liver during the prenatal and postnatal periods is of critical importance for understanding hepatic diseases[1]. We read with great interest the pilot study by Kotb et al[2] published in World Journal of Clinical Pediatrics. The authors demonstrated significantly reduced serum cytochrome P450 1A2 (CYP1A2) levels in neonates with biliary atresia and neonatal hepatitis compared to healthy controls. This finding is valuable as it highlights the potential role of detoxification mechanisms within the framework of the Kotb disease hypothesis. However, there are critical methodological issues regarding the interpretation of these results that warrant further discussion.

First and foremost is the causality dilemma. The study presents low CYP1A2 levels as an inherent defect and a susceptibility factor for the disease. However, it is well established that cytochrome P450 enzymes, particularly CYP1A2, are downregulated during systemic inflammation and liver injury[3,4]. The fact that enzyme levels were not normalized against liver function tests or synthetic capacity markers (albumin, international normalized ratio) leaves a crucial question unanswered: Is this reduction a primary genetic defect or merely a secondary consequence of hepatocellular dysfunction?

Secondly, the use of the term “defect” implies a genetic origin. Although the authors link this reduction to the Kotb disease variant (GSTM1 deficiency + aflatoxin exposure), neither CYP1A2 genotyping nor confirmation of aflatoxin/GSTM1 status was performed in the current cohort. Labeling this phenotypic reduction as an inherited “detoxification defect” without genetic validation remains speculative[5]. The study presents low CYP1A2 levels as an inherent ‘defect’. However, a clear distinction must be made: A ‘defect’ implies a permanent innate deficiency, whereas ‘downregulation’ represents an acquired reduction. In the context of neonatal hepatitis, the inflammatory milieu likely triggers a secondary suppression of CYP enzymes. Without excluding this mechanism, attributing the findings solely to a susceptibility factor remains premature.

Thirdly, the approach to enzyme measurement warrants careful consideration. CYP1A2 is an intracellular enzyme, and its activity is best assessed in liver tissue or via specific probe drug metabolism assays. Since enzyme-linked immunosorbent assay (ELISA) measures protein abundance rather than catalytic function, it may overestimate or underestimate the actual metabolic clearance capacity in the context of liver disease[6]. To address the limitations of protein quantification via ELISA, we propose two concrete experimental advancements. Utilizing a non-invasive caffeine breath test or plasma caffeine clearance ratios (measured via liquid chromatography-tandem mass spectrometry) would provide a direct assessment of CYP1A2’s catalytic capacity, which protein levels alone may not reflect. Beyond simple genotyping, employing single-cell multi-omics can decode the cellular heterogeneity and microenvironmental shifts in biliary diseases[7]. Furthermore, considering the Gut-X axis and microbiota-associated metabolites is essential, as these factors significantly influence metabolic susceptibility and hepatic health[8,9].

CONCLUSION

In conclusion, Kotb et al[2] provide an important warning regarding drug metabolism and safety (particularly related to ursodeoxycholic acid) in cholestatic infants. To further strengthen the interesting claims made in the study, the literature should be supplemented with large-scale studies on newborns[10]. Before accepting low CYP1A2 levels as the cause of pathogenesis, further research involving larger sample sizes, genetic sequencing, and transcriptomic analysis is necessary to distinguish between congenital disorders and secondary suppression.