Cytochrome P450 Isozymes Involved in Aromatic Hydroxylation and Side-Chain N-Desisopropylation of Alprenolol in Rat Liver Microsomes

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Alprenolol 4-hydroxylation and N-desisopropylation in liver microsomes from male Wistar rats were kinetically analyzed to be biphasic. In the 4-hydroxylation at a low substrate concentration (5μM), significant strain [Wistar>Dark Agouti (DA)] and sex (male>female) differences were observed, and the differences decreased at a high substrate concentration (1mM). In the N-desisopropylation, only a strain difference (Wistar>DA) was observed at the low substrate concentration. Cytochrome P450BTL (P450BTL, corresponding to CYP2D2) in a reconstituted system with 5μM alprenolol had high 4-hydroxylase activity, which was about 10 times that of P450ml corresponding to CYP2C11,and N-desisopropylase activity at a similar extent to P450ml. The two microsomal activities at 5μM alprenolol were efficiently decreased by antibodies against P450BTL and by sparteine, a typical substrate of the CYP2D subfamily. Polyclonal antibodies against P450ml and P450PB-1 (corresponding to CYP3A2) partially suppressed only N-desalkylation at 5μM, whereas they reduced the two activities at 1mM. P450ml showed a high N-desisopropylase activity at a substrate concentration of 1mM, where the sex difference was not observed. Furthermore, P450PB-2 corresponding to CYP2C6,which is one of the major P450 isozymes in female rats, also had 4-hydroxylase and N-desalkylase activities. These results suggest that a CYP2D isozyme(s) is the primary enzyme in alprenolol 4-hydroxylation and N-desisopropylation in a lower substrate concentration range, and that the involvement of some male-specific P450 isozyme(s) other than CYP2C11 or CYP3A2 may cause the sex difference in the 4-hydroxylation. In a higher substrate concentration range, CYP2C11 is thought to play a major role particularly in N-desisopropylation in male rats. In female rats, some major constitutive P450 isozyme(s) with a relatively high K_m value (e.g., CYP2C6) may be involved in the metabolism of alprenolol, resulting in the disappearance of the sex difference.
1995-08-15

Cytochrome P450 Isozymes Involved in Aromatic Hydroxylation and Side-Chain N-Desisopropylation of Alprenolol in Rat Liver Microsomes

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