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5. GENETIC BASIS OF SUBSTANCE DEPENDENCE

ALDH2*1 is a very active form found at high frequency among most ethnic
populations, while the ALDH2*2 is inactive (or has very low activity) and is
found at high frequency among Asians (e.g. Chinese, Japanese and Korean
people). The ALDH2*2 has been demonstrated to be associated with
substantial protection from alcohol in Japanese (Maezawa et al., 1995;
Nakamura et al., 1996; Okamoto et al., 2001), Han Chinese (Chen et al., 1999),
and Korean people (Lee et al., 2001). Genetic variation in ALDH2 in multiple
ethnic groups alters the amount of ethanol consumed ( Tanaka et al., 1997;
Sun et al., 1999; Okamoto et al., 2001) and risk for binge drinking (Luczak et
al., 2001). An association with liver disease was observed in some (Chao et
al., 1997) but not all studies (Maruyama et al., 1999; Lee et al., 2001), and may
be due to the effect on levels of consumption. Other variants of the ALDH2
are also under investigation.

Alcohol dehydrogenase

Alcohol dehydrogenase (ADH) metabolizes alcohol to acetaldehyde; it exists
as a polygene family on chromosome 4p, which has been linked to alcohol
dependence.
ADH2*2 allele frequency is lower in populations with alcohol dependence,
indicating a protective role for ADH2*2 (Thomasson et al., 1994; Maezawa et
al., 1995; Nakamura et al., 1996; Chen et al., 1999). For example, in aboriginal
peoples of Taiwan (Thomasson et al., 1994) who have low frequencies of the
protective allele ALDH2*2 (and thus would be more vulnerable), but who also
have high frequencies of ADH2*2, (which is also protective), the protective
effect of ADH2*2 is evident. This has also been seen in a Jewish population
(Neumark et al., 1998; Shea et al., 2001). One study found that the ADH2
genotype had significant effects on both consumption and dependence in
men, but not in women (Whitfield et al., 1998). ADH2 polymorphism was
also associated with the risk of chronic alcohol-induced pancreatitis
(Maruyama et al., 1999).

CYP2E1
Cytochrome P-450 2E1 (CYP2E1) is a hepatic enzyme that also metabolizes
ethanol to acetaldehyde. In humans, the levels of hepatic CYP2E1 activity
were found to vary by 15-fold. The 2E1 gene appears to be genetically
polymorphic and rare 2E1 variant alleles are associated with altered ethanol
metabolism (Watanabe, Hayashi & Kawajiri, 1994; Fairbrother et al., 1998;
McCarver et al., 1998; Hu et al., 1999; Sun et al., 1999; Yoshihara et al., 2000a).
Nicotine increases hepatic CYP2E1 in animal models, and smokers have
higher CYP2E1 activity than non-smokers (Benowitz, Jacob & Saunders, 1999;
Howard et al., 2001). Consistent with this, data from twin studies suggest that
cigarette smoking may contribute to the development of tolerance to the
effects of alcohol and a diminished sense of intoxication (Madden et al., 1995;

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