Carboxylesterase major forms

In analogy to other enzyme systems, the superfamily of carboxylesterases has been divided into families and subfamilies based on sequence homology (Table 2.7) [79], The major family, CES 1, all exhibit >60% homology with human carboxylesterase HU 1. This family is divided into subfamilies, namely CES 1A, IB, and 1C. As shown in Table 2.7, the enzyme CES 1A1 includes the major forms of human carboxylesterases (>99.5% homology). 

In humans, the principal route of metabolism of cocaine is by hydrolysis of the ester linkages. Pseudocholinesterase and liver esterases produce the inactive metabolite, ecgonine methyl ester (EME) (Figure 4.5). The second major metabolite, BE, is formed spontaneously at physiological pH. In addition, there is evidence that BE may be formed enzymatically from cocaine by liver carboxylesterases. N-Demethylation of BE produces benzoylnorecgonine. Further metabolism of EME and BE produces ecgonine. Further hydrolysis of cocaine and BE produces minor metabolites, meta- and para-hydroxy-cocaine and -BE. The proportion of each metabolite produced and the activity of the individual metabolites have yet to be completely determined. 

SN-38, the major active metabolite of irinotecan formed from hepatic carboxylesterase, accounts for both the cytotoxic activity and the gastrointestinal side-effects. The metabolism of SN-38 is catalysed via CYP3A4 to a much less active metabolite - aminopentane carboxylic acid,... 

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