High Frequency of CYP3A4*1B among Opiate Dependent Patients in Malaysia

Abstract

The sharing of injection needles among drug user is a leading cause for the spread of HIV/AIDS. Malaysia introduced methadone as a management of heroin dependents to reduce HIV spread. Methadone has variable pharmacokinetics and CYP3A4 has been implicated in its metabolism. The objective of this study therefore was to determine if polymorphisms exist with CYP3A4 among opiate users in Malaysia. This study was approved by Ethics Committees at University of Malaya and Universiti Sains Malaysia. Control subjects comprised blood donors, students and residents of a village. Opiate-dependents were from methadone clinics and drop-in centers. They signed a written-informed consent to participate and gave blood for DNA CYP3A4 genotyping. DNA was extracted using QIAgen DNA mini kit. A nested two-step allele specific PCR method was developed to detect CYP3A4*1B, CYP3A4*3, CYP3A4*4, CYP3A4*5, CYP3A4*6, CYP3A4*7, CYP3A4*8, CYP3A4*9, CYP3A4*10, CYP3A4*11, CYP3A4*12, CYP3A4*13, CYP3A4*14, CYP3A4*15 and CYP3A4*16. Normal controls comprised Malays, Chinese and Indians but opiate-dependent subjects were majority Malay males. Control subjects all carried the wild-type gene. Mutant CYP3A4*1B allele was found in 2.17% of opiate-dependent subjects. Our results revealed that CYP3A4 was not polymorphic among Malaysian Malays, Chinese and Indians who were not opiate-dependent. To date, we are not aware of any study to associate CYP3A4 polymorphism and heroin addiction. It is conceivable that altered CYP3A4 function may contribute towards addiction liabilities in subsets of individuals. We conclude that CYP3A4 is polymorphic among heroin-dependent individuals. The mutation, CYP3A4*1B is not silent. This may have implications on heroin addiction liability as well as on dose requirements for MMT and HAART.