Neonatal cholestasis is associated with cytochrome P450 1A2 detoxification defect: A single center pilot study

Abstract

BACKGROUND Evidence supports that biliary atresia (BA) in Egyptian infants is an aflatoxin-induced cholangiopathy acquired perinatally in infants with glutathione S-transferase M1 deficiency: The Kotb disease BA variant. This inability to detoxify aflatoxins leads to progressive inflammatory adhesions and obliterative cholangiopathy early in life. AIM To investigate the cytochrome P450 1A2 (CYP1A2) detoxification enzyme levels in neonates with confirmed BA. METHODS This prospective descriptive analytical study estimated CYP1A2 detoxification enzyme levels using enzyme-linked immunosorbent assay in 20 neonates with confirmed BA. The level CYP1A2 was also estimated in a control group of 20 infants with neonatal hepatitis (NH) and 20 age- and sex-matched healthy infants. RESULTS The mean age at enrollment in the study was 2.16 ± 0.58 months, 2.51 ± 1.05 months and 1.9 ± 0.81 months for the BA, NH and control group (P = 0.42). The mean ± SD of CYP1A2 among BA, NH and control group was 13.58 ± 9.73, 9.59 ± 9.95 and 31.68 ± 12.33 (P = 0.001). Within 3 months of follow up, of those with BA who underwent portoenterostomy 12 (60%) had successful outcome and cleared the jaundice, 5 (25%) had a stationary course and did not clear the jaundice while 3 (15%) died. The cholestasis resolved in 5 (25%) of the NH group, and improved in 15 (75%). CYP1A2 level did not correlate with age (r = 0.1559, P = 0.336), or total bilirubin level (r = 0.156, P = 0.336), alanine aminotransferase (r = -0.166, P = 0.305), aspartate aminotransferase (r = 0.091, P = 0.576), gamma glutamyl transferase (r = -0.0027, P = 0.99), alkaline phosphatase (r = 0.1059, P = 0.515), or outcome (r = 1.565, P = 0.23). A low CYP1A2 predicted a susceptibility to cholestasis by logistic regression (P = 0.000, 95% confidence interval: 0.8224-0.9327). CONCLUSION Significantly low serum CYP1A2 was frequent among infants with BA and NH compared to the control group. The low serum CYP1A2 compromises the detoxification ability of neonates with cholestasis and may alter the pharmacokinetics of commonly used drugs. Careful consideration to drug dosing and toxicity risk should be given to those neonates. Further research on drug pharmacokinetics and detoxification in neonates with cholestasis is recommended.